Benzamide-containing inhibitors of farnesyl-protein transferase

ABSTRACT

The present invention comprises peptidomimetic compounds which comprise a suitably substituted aminoalkylbenzamide moiety. The instant compounds inhibit the farnesyl protein transferase enzyme and the farnesylation of certain proteins. Furthermore, the instant farnesyl protein transferase inhibitors differ from those previously described as inhibitors of farnesyl-protein transferase in that they do not have a thiol moiety. The lack of the thiol offers unique advantages in terms of improved pharmacokinetic behavior in animals, prevention of thiol-dependent chemical reactions, such as rapid autoxidation and disulfide formation with endogenous thiols, and reduced systemic toxicity. Further contained in this invention are chemotherapeutic compositions containing these farnesyl transferase inhibitors and methods for their production.

BACKGROUND OF THE INVENTION

The Ras protein is part of a signalling pathway that links cell surfacegrowth factor receptors to nuclear signals initiating cellularproliferation. Biological and biochemical studies of Ras action indicatethat Ras functions like a G-regulatory protein. In the inactive state,Ras is bound to GDP. Upon growth factor receptor activation Ras isinduced to exchange GDP for GTP and undergoes a conformational change.The GTP-bound form of Ras propagates the growth stimulatory signal untilthe signal is terminated by the intrinsic GTPase activity of Ras, whichreturns the protein to its inactive GDP bound form (D. R. Lowy and D. M.Willumsen, Ann. Rev. Biochem. 62:851-891 (1993)). Mutated ras genes arefound in many human cancers, including colorectal carcinoma, exocrinepancreatic carcinoma, and myeloid leukemias. The protein products ofthese genes are defective in their GTPase activity and constitutivelytransmit a growth stimulatory signal.

Ras must be localized to the plasma membrane for both normal andoncogenic functions. At least 3 post-translational modifications areinvolved with Ras membrane localization, and all 3 modifications occurat the C-terminus of Ras. The Ras C-terminus contains a sequence motiftermed a "CAAX" or "Cys-Aaa¹ -Aaa² -Xaa" box (Cys is cysteine, Aaa is analiphatic amino acid, the Xaa is any amino acid) (Willumsen et al.,Nature 310:583-586 (1984)). Depending on the specific sequence, thismotif serves as a signal sequence for the enzymes farnesyl-proteintransferase or geranylgeranyl-protein transferase, which catalyze thealkylation of the cysteine residue of the CAAX motif with a C₁₅ or C₂₀isoprenoid, respectively. (S. Clarke., Ann. Rev. Biochem. 61:355-386(1992); W. R. Schafer and J. Rine, Ann. Rev. Genetics 30:209-237(1992)). The Ras protein is one of several proteins that are known toundergo post-translational farnesylation. Other farnesylatedproteins.include the Ras-related GTP-binding proteins such as Rho,fungal mating factors, the nuclear lamins, and the gamma subunit oftransducin. James, et al., J. Biol. Chem. 269, 14182 (1994) haveidentified a peroxisome associated protein Pxf which is alsofarnesylated. James, et al., have also suggested that there arefarnesylated proteins of unknown structure and function in addition tothose listed above

Inhibition of farnesyl-protein transferase has been shown to block thegrowth of Ras-transformed cells in soft agar and to modify other aspectsof their transformed phenotype. It has also been demonstrated thatcertain inhibitors of farnesyl-protein transferase selectively block theprocessing of the Ras oncoprotein intracellularly (N. E. Kohl et al.,Science, 260:1934-1937 (1993) and G. L. James et al., Science,260:1937-1942 (1993). Recently, it has been shown that an inhibitor offarnesyl-protein transferase blocks the growth of ras-dependent tumorsin nude mice (N. E. Kohl et al., Proc. Natl. Acad. Sci U.S.A.,91:9141-9145 (1994).

Indirect inhibition of farnesyl-protein transferase in vivo has beendemonstrated with lovastatin (Merck & Co., Rahway, N.J.) and compactin(Hancock et al., ibid; Casey et al., ibid; Schafer et al., Science245:379 (1989)). These drugs inhibit HMG-CoA reductase, the ratelimiting enzyme for the production of polyisoprenoids including farnesylpyrophosphate. Farnesyl-protein transferase utilizes farnesylpyrophosphate to covalently modify the Cys thiol group of the Ras CAAXbox with a farnesyl group (Reiss et al., Cell 62:81-88 (1990); Schaberet al., J. Biol. Chem., 265:14701-14704 ( 1990); Schafer et al.,Science, 249:1133-1139 (1990); Manne et al., Proc. Natl. Acad. Sci USA,87:7541-7545 (1990)). Inhibition of farnesyl pyrophosphate biosynthesisby inhibiting HMG-CoA reductase blocks Ras membrane localization incultured cells. However, direct inhibition of farnesyl-proteintransferase would be more specific and attended by fewer side effectsthan would occur with the required dose of a general inhibitor ofisoprene biosynthesis.

Inhibitors of farnesyl-protein transferase (FPTase) have been describedin two general classes. The first are analogs of farnesyl diphosphate(FPP), while the second class of inhibitors is related to the proteinsubstrates (e.g., Ras) for the enzyme. In the peptide derived class ofinhibitors, a subclass of inhibitors has been described which generallycomprises cysteine containing molecules that are related to the CAAXmotif that is the signal for protein prenylation. (Schaber et al., ibid;Reiss et. al., ibid; Reiss et al., PNAS, 88:732-736 (1991)). Suchinhibitors may inhibit protein prenylation while serving as alternatesubstrates for the farnesyl-protein transferase enzyme, or may be purelycompetitive inhibitors (U.S. Pat. No. 5,141,851, University of Texas; N.E. Kohl et al., Science, 260:1934-1937 (1993); Graham, et al., J. Med.Chem., 37, 725 (1994)). In general, deletion of the thiol from apeptidyl CAAX derivative has been shown to dramatically reduce theinhibitory potency of the compound. However, the thiol group potentiallyplaces limitations on the therapeutic application of FPTase inhibitorswith respect to pharmacokinetics, pharmacodynamics and toxicity.Therefore, a functional replacement for the thiol is desirable. With theexception of a group of antibiotics known as the pepticinnamins (Omura,et al., J. Antibiotics 46:222 (1993)), non-thiol FPTase inhibitors thatare competitive with the Ras substrate have not been described.

Another subclass of the peptide derived inhibitors which comprisespeptidomimetic compounds wherein the central AA portion of the CAAXmotif has been replaced by 3-aminobenzoic acid and 3-aminomethylbenzoicacid spacers has recently been described (M. Nigam et al. J. Biol.Chem., 268:20695-20698 (1993), Y. Qian et al. J. Biol. Chem.,269:12410-12413 (1994)). FPTase peptidomimetic inhibitors furtherlacking a C-terminus peptidyl moiety (wherein the X peptide has beenreplaced by a non-peptide moiety) have also been recently described (A.Vogt et al. J. Biol. Chem., 270:660-664 (1995)). All of the compounds inthis second subclass of peptide derived inhibitors retain the thiolmoiety.

It is, therefore, an object of this invention to develop non-peptidecompounds that do not have a thiol moiety, and that will inhibitfarnesyl-protein transferase and thus, the post-translationalfarnesylation of proteins. It is a further object of this invention todevelop chemotherapeutic compositions containing the compounds of thisinvention and methods for producing the compounds of this invention.

SUMMARY OF THE INVENTION

The present invention includes substituted aminoalkylbenzamide andaminobenzamide analogs which inhibit the farnesyl-protein transferase,chemotherapeutic compositions containing the compounds of thisinvention, and methods for producing the compounds of this invention.Furthermore these analogs differ from those previously described asinhibitors of farnesyl-protein transferase in that they do not have athiol moiety. The lack of the thiol offers unique advantages in terms ofimproved pharmacokinetic behavior in animals, prevention ofthiol-dependent chemical reactions, such as rapid autoxidation anddisulfide formation with endogenous thiols, and reduced systemictoxicity.

The compounds of this invention are illustrated by the formulae:##STR1##

DETAILED DESCRIPTION OF THE INVENTION

The compounds of this invention are useful in the inhibition offarnesyl-protein transferase and the farnesylation of certain proteins.

In a first embodiment of this invention, the farnesyl-proteintransferase inhibitors are illustrated by the formula I: ##STR2##wherein: R^(1a) and R^(1b) are independently selected from:

a) hydrogen,

b) aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, R¹⁰ O--, R¹¹S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--,R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) C₁ -C₆ alkyl unsubstituted or substituted by aryl, heterocycle,cycloalkyl, alkenyl, alkynyl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,CN, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, or R¹¹OC(O)--NR¹⁰ --;

R^(2a) and R^(2b) are independently selected from:

a) hydrogen,

b) C₁ -C₆ alkyl unsubstituted or substituted by alkenyl, R¹⁰ O--, R¹¹S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, N₃, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--,R¹⁰ OC(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) aryl, heterocycle, cycloalkyl, alkenyl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and

d) C₁ -C₆ alkyl substituted with an unsubstituted or substituted groupselected from aryl, heterocyclic and C₃ -C₁₀ cycloalkyl;

R^(3a) and R^(3b) are independently selected from:

a) a side chain of a naturally occurring amino acid,

b) an oxidized form of a side chain of a naturally occurring amino acidwhich is:

i) methionine sulfoxide, or

ii) methionine sulfone, and

c) substituted or unsubstituted C₁ -C₂₀ alkyl, C₂ -C₂₀ alkenyl, C₃ -C₁₀cycloalkyl, aryl or heterocyclic group, wherein the substituent isselected from F, Cl, Br, N(R¹⁰)₂, NO₂, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰C(O)NR¹⁰ --, CN, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃,--N(R¹⁰)₂, R¹¹ OC(O)NR¹⁰ -- and C₁ -C₂₀ alkyl, and

d) C₁ -C₆ alkyl substituted with an unsubstituted or substituted groupselected from aryl, heterocycle and C₃ -C₁₀ cycloalkyl; or

R^(3a) and R^(3b) are combined to form --(CH₂)_(s) -- wherein one of thecarbon atoms is optionally replaced by a moiety selected from: O,S(O)_(m), --NC(O)--, and --N(COR¹⁰)--;

R⁴ and R⁵ are independently selected from:

a) hydrogen, and

b) ##STR3## R⁷ is independently selected from: a) hydrogen,

b) aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F,Cl, Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, R¹⁰ ₂N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰--, and

c) C₁ -C₆ alkyl unsubstituted or substituted by aryl, heterocycle,cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R¹⁰ O--, R¹¹S(O)_(m) --, R¹⁰ C(O)NH--, CN, H₂ N--C(NH)--, R¹⁰ C(O)--, R¹⁰ OC(O)--,N₃, --N(R¹⁰)₂, or R¹⁰ OC(O)NH--;

R⁸ is selected from:

a) hydrogen,

b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R¹⁰ O--, R¹¹ S(O)_(m)--, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C--(N^(R) ¹⁰)--, R¹⁰ C(O)--, R¹⁰OC(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and

c) C₁ -C₆ alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl,Br, R¹⁰ O--,R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, (R¹⁰)₂ N--C(NR¹⁰)--,R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --;

R¹⁰ is independently selected from hydrogen, C₁ -C₆ alkyl, benzyl andaryl;

R¹¹ is independently selected from C₁ -C₆ alkyl and aryl;

A¹ and A² are independently selected from: a bond, --CH═CH--,--C.tbd.C--, --C(O)--, --C(O)NR¹⁰ --, --NR¹⁰ C(O)--, O, --N(R¹⁰)--,--S(O)₂ N(R¹⁰)--, --N(R¹⁰)S(O)₂ --, or S(O)_(m) ;

V is selected from:

a) hydrogen,

b) heterocycle,

c) aryl,

d) C₁ -C₂₀ alkyl wherein from 0 to 4 carbon atoms are replaced with a aheteroatom selected from O, S, and N, and

e) C₂ -C₂₀ alkenyl,

provided that V is not hydrogen if A¹ is S(O)_(m) and V is not hydrogenif A¹ is a bond, n is 0 and A² is S(O)_(m) ;

W is a heterocycle;

Z is independently H₂ or O;

m is 0, 1 or 2;

n is 0, 1, 2, 3 or 4;

p is 0, 1, 2, 3 or 4;

r is 0 to 5, provided that r is 0 when V is hydrogen;

s is 4 or 5; and

u is 0 or 1;

or the pharmaceutically acceptable salts thereof.

In a second embodiment of this invention the prodrugs of compounds offormula I are illustrated by the formula II: ##STR4## wherein: R^(1a)and R^(1b) are independently selected from:

a) hydrogen,

b) aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, R¹⁰ O--, R¹¹S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--,R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) C₁ -C₆ alkyl unsubstituted or substituted by aryl, heterocyclic,cycloalkyl, alkenyl, alkynyl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,CN, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, or R¹¹OC(O)--NR¹⁰ --;

R^(2a) and R^(2b) are independently selected from:

a) hydrogen,

b) C₁ -C₆ alkyl unsubstituted or substituted by alkenyl, R¹⁰ O--, R¹¹S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, N₃, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--,R¹⁰ OC(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) aryl, heterocycle, cycloalkyl, alkenyl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and

d) C₁ -C₆ alkyl substituted with an unsubstituted or substituted groupselected from aryl, heterocyclic and C₃ -C₁₀ cycloalkyl;

R^(3a) and R^(3b) are independently selected from:

a) a side chain of a naturally occurring amino acid,

b) an oxidized form of a side chain of a naturally occurring amino acidwhich is:

i) methionine sulfoxide, or

ii) methionine sulfone, and

c) substituted or unsubstituted C₁ -C₂₀ alkyl, C₂ -C₂₀ alkenyl, C₃ -C₁₀cycloalkyl, aryl or heterocyclic group,

wherein the substituent is selected from F, Cl, Br, N(R¹⁰)₂, NO₂, R¹⁰O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, R¹¹ OC(O)NR¹⁰ -- and C₁ -C₂₀ alkyl,and

d) C₁ -C₆ alkyl substituted with an unsubstituted or substituted groupselected from aryl, heterocycle and C₃ -C₁₀ cycloalkyl; or

R^(3a) and R^(3b) are combined to form --(CH₂)_(s) -- wherein one of thecarbon atoms is optionally replaced by a moiety selected from: O,S(O)_(m), --NC(O)--, and --N(COR¹⁰)--;

R⁴ and R⁵ are independently selected from:

a) hydrogen, and

b) ##STR5## R⁶ is a) substituted or unsubstituted C₁ -C₈ alkyl orsubstituted or unsubstituted C₅ -C₈ cycloalkyl, wherein the substituenton the alkyl is selected from:

1 ) aryl,

2) heterocycle,

3) --N(R¹¹)₂,

4) --OR¹⁰, or

b) ##STR6## R⁷ is independently selected from: a) hydrogen,

b) aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F,Cl, Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, R¹⁰ ₂N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰--, and

c) C₁ -C₆ alkyl unsubstituted or substituted by aryl, heterocycle,cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R¹⁰ O--, R¹¹S(O)_(m) --, R¹⁰ C(O)NH--, CN, H₂ N--C(NH)--, R¹⁰ C(O)--, R¹⁰ OC(O)--,N₃, --N(R¹⁰)₂, or R¹⁰ OC(O)NH--;

R8 is selected from:

a) hydrogen,

b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R¹⁰ O--, R¹¹ S(O)_(m)--, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C--(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰OC(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and

c) C₁ -C₆ alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl,Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, (R¹⁰)₂ N--C(NR¹⁰)--,R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --;

R¹⁰ is independently selected from hydrogen, C₁ -C₆ alkyl, benzyl andaryl;

R¹¹ is independently selected from C₁ -C₆ alkyl and aryl;

R¹² is independently selected from hydrogen and C₁ -C₆ alkyl;

R¹³ is independently selected from C₁ -C₆ alkyl;

A¹ and A² are independently selected from: a bond, --CH═CH--,--C.tbd.C--, --C(O)--, --C(O)NR¹⁰ --, --NR¹⁰ C(O)--, O, --N(R¹⁰)--,--S(O)₂ N(R¹⁰)--,--N(R¹⁰)S(O)₂ --, or S(O)_(m) ;

V is selected from:

a) hydrogen,

b) heterocycle,

c) aryl,

d) C₁ -C₂₀ alkyl wherein from 0 to 4 carbon atoms are replaced with a aheteroatom selected from O, S, and N, and

e) C₂ -C₂₀ alkenyl,

provided that V is not hydrogen if A¹ is S(O)_(m) and V is not hydrogenif A¹ is a bond, n is 0 and A² is S(O)_(m) ;

W is a heterocycle;

Z is independently H₂ or O;

m is 0, 1 or 2;

n is 0, 1, 2, 3 or 4;

p is 0, 1, 2, 3 or 4;

r is 0 to 5, provided that r is 0 when V is hydrogen;

s is 4 or 5; and

u is 0 or 1;

or the pharmaceutically acceptable salts thereof.

In a third embodiment of this invention, the inhibitors of farnesyltransferase are illustrated by the formula III: ##STR7## wherein: R¹ aand R^(1b) are independently selected from:

a) hydrogen,

b) aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, R¹⁰ O--, R¹¹S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, NO₂,l (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--,R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) C₁ -C₆ alkyl unsubstituted or substituted by aryl, heterocyclic,cycloalkyl, alkenyl, alkynyl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,CN, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, or R¹¹OC(O)--NR¹⁰ --;

R^(2a) and R^(2b) are independently selected from:

a) hydrogen,

b) C₁ -C₆ alkyl unsubstituted or substituted by alkenyl, R¹⁰ O--, R¹¹S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, N₃, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--,R¹⁰ OC(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) aryl, heterocycle, cycloalkyl, alkenyl, R¹⁰)--, R¹¹ S(O)_(m) --, R¹⁰C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and

d) C₁ -C₆ alkyl substituted with an unsubstituted or substituted groupselected from aryl, heterocyclic and C₃ -C₁₀ cycloalkyl;

R⁴ and R⁵ are independently selected from:

a) hydrogen, and

b) ##STR8## R⁷ is independently selected from: a) hydrogen,

b) aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F,Cl, Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, R¹⁰ ₂N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰--, and

c) C₁ -C₆ alkyl unsubstituted or substituted by aryl, heterocycle,cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R¹⁰ O--, R¹¹S(O)_(m) --, R¹⁰ C(O)NH--, CN, H₂ N--C(NH)--, R¹⁰ C(O)--, R¹⁰ OC(O)--,N₃, --N(R¹⁰)₂, or R¹⁰ OC(O)NH--;

R⁸ is selected from:

a) hydrogen,

b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R¹⁰ O--, R¹¹ S(O)_(m)--, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C--(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰OC(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and

c) C₁ -C₆ alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl,Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, (R¹⁰)₂ N--C(NR¹⁰)--,R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --;

R¹⁰ is independently selected from hydrogen, C₁ -C₆ alkyl, benzyl andaryl;

R¹¹ is independently selected from C₁ -C₆ alkyl and aryl;

A¹ and A² are independently selected from: a bond, --CH═CH--,--C.tbd.C--, --C(O)--, --C(O)NR¹⁰ --, --NR¹⁰ C(O)--, O, --N(R¹⁰)--,--S(O)₂ N(R¹⁰)--, --N(R¹⁰)S(O)₂ --, or S(O)_(m) ;

V is selected from:

a) hydrogen,

b) heterocycle,

c) aryl,

d) C₁ -C₂₀ alkyl wherein from 0 to 4 carbon atoms are replaced with a aheteroatom selected from O, S, and N, and

e) C₂ -C₂₀ alkenyl,

provided that V is not hydrogen if A¹ is S(O)_(m) and V is not hydrogenif A¹ is a bond, n is 0 and A² is S(O)_(m) ;

W is a heterocycle;

Z is independently H₂ or O;

m is 0, 1 or 2;

n is 0, 1, 2, 3 or 4;

p is 0, 1, 2, 3 or 4;

q is 0, 1 or 2;

r is 0 to 5, provided that r is 0 when V is hydrogen;

s is 4 or 5; and

u is 0or 1;

or the pharmaceutically acceptable salts thereof.

In a fourth embodiment of this invention the prodrugs of compounds offormula III are illustrated by the formula IV: ##STR9## wherein: R^(1a)and R^(1b) are independently selected from:

a) hydrogen,

b) aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, R¹⁰ O--, R¹¹S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--,R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) C₁ -C₆ alkyl unsubstituted or substituted by aryl, heterocyclic,cycloalkyl, alkenyl, alkynyl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,CN, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃,--N(R¹⁰)₂, or R¹¹OC(O)--NR¹⁰ --;

R^(2a) and R^(2b) are independently selected from:

a) hydrogen,

b) C₁ -C₆ alkyl unsubstituted or substituted by alkenyl, R¹⁰ O--, R¹¹S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, N₃, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--,R¹⁰ OC(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) aryl, heterocycle, cycloalkyl, alkenyl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and

d) C_(hd) 1 -C₆ alkyl substituted with an unsubstituted or substitutedgroup selected from aryl, heterocyclic and C₃ -C₁₀ cycloalkyl;

R⁴ and R⁵ are independently selected from:

a) hydrogen, and

b) ##STR10## R⁷ is independently selected from: a) hydrogen,

b) aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F,Cl, Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, R¹⁰ ₂N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰--, and

c) C₁ -C₆ alkyl unsubstituted or substituted by aryl, heterocycle,cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R¹⁰ O--, R¹¹S(O)_(m) --, R¹⁰ C(O)NH--, CN, H₂ N--C(NH)--, R¹⁰ C(O)--, R¹⁰ OC(O)--,N₃, --N(R¹⁰)₂, or R¹⁰ OC(O)NH--;

R8 is selected from:

a) hydrogen,

b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R¹⁰ O--, R¹¹ S(O)_(m)--, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C--(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰OC(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and

c) C₁ -C₆ alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl,Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, (R¹⁰)₂ N--C(NR¹⁰)--,R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --;

R¹⁰ is independently selected from hydrogen, C₁ -C₆ alkyl, benzyl andaryl;

R¹¹ is independently selected from C₁ -C₆ alkyl and aryl;

A¹ and A² are independently selected from: a bond, --CH═CH--,--C.tbd.C--, --C(O)--, --C(O)NR¹⁰ --, --NR¹⁰ C(O)--, O, --N(R¹⁰)--,--S(O)₂ N(R¹⁰)--, --N(R¹⁰)S(O)₂ --, or S(O)_(m) ;

V is selected from:

a) hydrogen,

b) heterocycle,

c) aryl,

d) C₁ -C₂₀ alkyl wherein from 0 to 4 carbon atoms are replaced with a aheteroatom selected from O, S, and N, and

e) C₂ -C₂₀ alkenyl,

provided that V is not hydrogen if A¹ is S(O)_(m) and V is not hydrogenif A¹ is a bond, n is 0 and A² is S(O)_(m) ;

W is a heterocycle;

Z is independently H₂ or O;

m is 0, 1 or 2;

n is 0, 1, 2, 3 or 4;

p is 0, 1, 2, 3 or 4;

q is 0, 1 or 2;

r is 0 to 5, provided that r is 0 when V is hydrogen;

s is 4 or 5; and

u is 0or 1;

or the pharmaceutically acceptable salts thereof.

In a more preferred embodiment of this invention, the Ras farnesyltransferase inhibitors are illustrated by the Formula Ia: ##STR11##wherein: R^(1a) is independently selected from: hydrogen or C₁ -C₆alkyl;

R^(1b) is independently selected from:

a) hydrogen,

b) aryl, heterocycle, cycloalkyl, R¹⁰ O--, --N(R¹⁰)₂ or alkenyl,

c) C₁ -C₆ alkyl unsubstituted or substituted by aryl, heterocycle,cycloalkyl, alkenyl, R¹⁰ O--, or --N(R¹⁰)₂ ;

R^(2a) is selected from:

a) hydrogen,

b) C₁ -C₆ alkyl unsubstituted or substituted by alkenyl, R¹⁰ O--, R¹¹S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, N₃, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--,R¹⁰ OC(O)--, --N(R¹⁰ ₂, or R¹¹ OC(O)NR¹⁰ --,

c) aryl, heterocycle, cycloalkyl, alkenyl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and

d) C₁ -C₆ alkyl substituted with an unsubstituted or substituted groupselected from aryl, heterocyclic and C₃ -C₁₀ cycloalkyl;

R^(2b) is hydrogen;

R^(3a) and R^(3b) are independently selected from:

a) a side chain of a naturally occurring amino acid,

b) an oxidized form of a side chain of a naturally occurring amino acidwhich is:

i) methionine sulfoxide, or

ii) methionine sulfone,

c) substituted or unsubstituted C₁ -C₁₀ alkyl, C₂ -C₁₀ alkenyl, C₃ -C₁₀cycloalkyl, aryl or heterocyclic group,

wherein the substituent is selected from F, Cl, Br, NO₂, R¹⁰ O--, R¹¹S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰OC(O)--, N₃, --N(R¹⁰)₂, R¹¹ OC(O)NR¹⁰ -- and C₁ -C₂₀ alkyl, and

d) C₁ -C₆ alkyl substituted with an unsubstituted or substituted groupselected from aryl, heterocycle and C₃ -C₁₀ cycloalkyl;

R⁴ and R⁵ are independently selected from:

a) hydrogen, and

b) ##STR12## R⁷ is independently selected from: a) hydrogen,

b) C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₁ -C₆ perfluoroalkyl,F, Cl, R¹⁰ O--, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰C(O)--, R¹⁰ OC(O)--, N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and

c) C₁ -C₆ alkyl substituted by C₁ -C₆ perfluoroalkyl, R¹⁰ O--, R¹⁰C(O)NR¹⁰ --, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, --N(R¹⁰)₂, orR¹¹ OC(O)NR¹⁰ --;

R⁸ is selected from:

a) hydrogen,

b) C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₁ -C₆ perfluoroalkyl, F, Cl, R¹⁰O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰C(O)--, R¹⁰ OC(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and

c) C₁ -C₆ alkyl unsubstituted or substituted by C₁ -C₆ perfluoroalkyl,F, Cl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, (R¹⁰)₂N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --;

R¹⁰ is independently selected from hydrogen, C₁ -C₆ alkyl, benzyl andaryl;

R¹¹ is independently selected from C₁ -C₆ alkyl and aryl;

A¹ and A² are independently selected from: a bond, --CH═CH--,--C.tbd.C--, --C(O)--, --C(O)NR¹⁰ --, O, --N(R¹⁰)--, or S(O)_(m) ;

V is selected from:

a) hydrogen,

b) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl,thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl,isoquinolinyl, and thienyl,

c) aryl,

d) C₁ -C₂₀ alkyl wherein from 0 to 4 carbon atoms are replaced with a aheteroatom selected from O, S, and N, and

e) C₂ -C₂₀ alkenyl, and

provided that V is not hydrogen if A¹ is S(O)_(m) and V is not hydrogenif A¹ is a bond, n is 0 and A² is S(O)_(m) ;

W is a heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl,thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, orisoquinolinyl;

Z is independently H₂ or O;

m is 0, 1 or 2;

n is 0, 1, 2, 3 or 4;

p is 0, 1, 2, 3 or 4;

r is 0 to 5, provided that r is 0 when V is hydrogen; and

u is 0or 1;

or the pharmaceutically acceptable salts thereof.

In a second more preferred embodiment of this invention, the prodrugs ofthe preferred compounds of Formula I are illustrated by the Formula IIa:##STR13## R^(1a) is independently selected from: hydrogen or C₁ -C₆alkyl;

R^(1b) is independently selected from:

a) hydrogen,

b) aryl, heterocycle, cycloalkyl, R¹⁰ O--, --N(R¹⁰)₂ or alkenyl,

c) C₁ -C₆ alkyl unsubstituted or substituted by aryl, heterocycle,cycloalkyl, alkenyl, R¹⁰ O--, or --N(R¹⁰)₂ ;

R^(2a) is selected from:

a) hydrogen,

b) C₁ -C₆ alkyl unsubstituted or substituted by alkenyl, R¹⁰ O--, R¹¹S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, N₃, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--,R¹⁰ OC(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) aryl, heterocycle, cycloalkyl, alkenyl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and

d) C₁ -C₆ alkyl substituted with an unsubstituted or substituted groupselected from aryl, heterocyclic and C₃ -C₁₀ cycloalkyl;

R^(2b) is hydrogen;

R^(3a) and R^(3b) are independently selected from:

a) a side chain of a naturally occurring amino acid,

b) an oxidized form of a side chain of a naturally occurring amino acidwhich is:

i) methionine sulfoxide, or

ii) methionine sulfone,

c) substituted or unsubstituted C₁ -C₁₀ alkyl, C₂ -C₁₀ alkenyl, C₃ -C₁₀cycloalkyl, aryl or heterocyclic group,

wherein the substituent is selected from F, Cl, Br, NO₂, R¹⁰ O--, R¹¹S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰OC(O)--, N₃, --N(R¹⁰)₂, R¹¹ OC(O)NR¹⁰ -- and C₁ -C₂₀ alkyl, and

d) C₁ -C₆ alkyl substituted with an unsubstituted or substituted groupselected from aryl, heterocycle and C₃ -C₁₀ cycloalkyl;

R⁴ and R⁵ are independently selected from:

a) hydrogen, and

b) ##STR14## R⁶ is a) substituted or unsubstituted C₁ -C₈ alkyl orsubstituted or unsubstituted C₅ -C₈ cycloalkyl, wherein the substituenton the alkyl is selected from:

1) aryl,

2) heterocycle,

3) --N(R¹¹)₂,

4) --OR¹⁰, or

b) ##STR15## R⁷ is independently selected from: a) hydrogen,

b) C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkyl, C₁ -C₆ perfluoroalkyl, F,Cl, R¹⁰ O--, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--,R¹⁰ OC(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and

c) C₁ -C₆ alkyl substituted by C₁ -C₆ perfluoroalkyl, R¹⁰ O--, R¹⁰C(O)NR¹⁰ --, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, --N(R¹⁰)₂, orR¹¹ OC(O)NR¹⁰ --;

R⁸ is selected from:

a) hydrogen,

b) C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₁ -C₆ perfluoroalkyl, F, Cl, R¹⁰O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰C(O)--, R¹⁰ OC(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and

c) C₁ -C₆ alkyl unsubstituted or substituted by C₁ -C₆ perfluoroalkyl,F, Cl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, (R¹⁰)₂N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --;

R¹⁰ is independently selected from hydrogen, C₁ -C₆ alkyl, benzyl andaryl;

R¹¹ is independently selected from C₁ -C₆ alkyl and aryl;

R¹² is independently selected from hydrogen and C₁ -C₆ alkyl;

R¹³ is independently selected from C₁ -C₆ alkyl;

A¹ and A² are independently selected from: a bond, --CH═CH--,--C.tbd.C--, --C(O)--, --C(O)NR¹⁰ --, O, --N(R¹⁰)--, or S(O)_(m) ;

V is selected from:

a) hydrogen,

b) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl,thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl,isoquinolinyl, and thienyl,

c) aryl,

d) C₁ -C₂₀ alkyl wherein from 0 to 4 carbon atoms are replaced with a aheteroatom selected from O, S, and N, and

e) C₂ -C₂₀ alkenyl, and

provided that V is not hydrogen if A¹ is S(O)_(m) and V is not hydrogenif A¹ is a bond, n is 0 and A² is S(O)_(m) ;

W is a heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl,thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, orisoquinolinyl;

Z is independently H₂ or O;

m is 0, 1 or 2;

n is 0, 1, 2, 3 or 4;

p is 0, 1, 2, 3 or 4;

r is 0 to 5, provided that r is 0 when V is hydrogen; and

u is 0 or 1;

or the pharmaceutically acceptable salts thereof.

In a third more preferred embodiment of this invention, the inhibitorsof farnesyl transferase are illustrated by the formula IIIa: ##STR16##wherein: R^(1a) is independently selected from: hydrogen or C₁ -C₆alkyl;

R^(1b) is independently selected from:

a) hydrogen,

b) aryl, heterocycle, cycloalkyl, R¹⁰ O--, --N(R¹⁰)₂ or alkenyl,

c) C₁ -C₆ alkyl unsubstituted or substituted by aryl, heterocycle,cycloalkyl, alkenyl, R¹⁰ O--, or --N(R¹⁰)₂ ;

R^(2a) is selected from:

a) hydrogen,

b) C₁ -C₆ alkyl unsubstituted or substituted by alkenyl, R¹⁰ O--, R¹¹S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, N₃, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--,R¹⁰ OC(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) aryl, heterocycle, cycloalkyl, alkenyl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and

d) C₁ -C₆ alkyl substituted with an unsubstituted or substituted groupselected from aryl, heterocyclic and C₃ -C₁₀ cycloalkyl;

R^(2b) is hydrogen;

R⁴ and R⁵ are independently selected from:

a) hydrogen, and

b) ##STR17## R⁷ is independently selected from: a) hydrogen,

b) C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₁ -C₆ perfluoroalkyl,F, Cl, R¹⁰ O--, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰C(O)--, R¹⁰ OC(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and

c) C₁ -C₆ alkyl substituted by C₁ -C₆ perfluoroalkyl, R¹⁰ O--, R¹⁰C(O)NR¹⁰ --, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, --N(R¹⁰)₂, orR¹¹ OC(O)NR¹⁰ --;

R⁸ is selected from:

a) hydrogen,

b) C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₁ -C₆ perfluoroalkyl, F, Cl, R¹⁰O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰C(O)--, R¹⁰ OC(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and

c) C₁ -C₆ alkyl unsubstituted or substituted by C₁ -C₆ perfluoroalkyl,F, Cl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, (R¹⁰)₂N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --;

R¹⁰ is independently selected from hydrogen, C₁ -C₆ alkyl, benzyl andaryl;

R¹¹ is independently selected from C₁ -C₆ alkyl and aryl;

A¹ and A² are independently selected from: a bond, --CH═CH--,--C.tbd.C--, --C(O)--, --C(O)NR¹⁰ --, O, --N(R¹⁰)--, or S(O)_(m) ;

V is selected from:

a) hydrogen,

b) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl,thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl,isoquinolinyl, and thienyl,

c) aryl,

d) C₁ -C₂₀ alkyl wherein from 0 to 4 carbon atoms are replaced with a aheteroatom selected from O, S, and N, and

e) C₂ -C₂₀ alkenyl, and

provided that V is not hydrogen if A¹ is S(O)_(m) and V is not hydrogenif A¹ is a bond, n is 0 and A² is S(O)_(m) ;

W is a heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl,thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, orisoquinolinyl;

Z is independently H₂ or O;

m is 0, 1 or 2;

n is 0, 1, 2, 3 or 4;

p is 0, 1, 2, 3 or 4;

q is 0, 1 or 2;

r is 0 to 5, provided that r is 0 when V is hydrogen; and

u is 0 or 1;

or the pharmaceutically acceptable salts thereof.

In a fourth more preferred embodiment of this invention, the prodrugs ofthe preferred compounds of Formula III are illustrated by the FormulaIVa: ##STR18## wherein R^(1a) is independently selected from: hydrogenor C₁ -C₆ alkyl;

R^(1b) is independently selected from:

a) hydrogen,

b) aryl, heterocycle, cycloalkyl, R¹⁰ O--, --N(R¹⁰)₂ or alkenyl,

c) C₁ -C₆ alkyl unsubstituted or substituted by aryl, heterocycle,cycloalkyl, alkenyl, R¹⁰ O--, or --N(R¹⁰)₂ ;

R^(2a) is selected from:

a) hydrogen,

b) C₁ -C₆ alkyl unsubstituted or substituted by alkenyl, R¹⁰ O--, R¹¹S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, N₃, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--,R¹⁰ OC(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) aryl, heterocycle, cycloalkyl, alkenyl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and

d) C₁ -C₆ alkyl substituted with an unsubstituted or substituted groupselected from aryl, heterocyclic and C₃ -C₁₀ cycloalkyl;

R^(2b) is hydrogen;

R⁴ and R⁵ are independently selected from:

a) hydrogen, and

b) ##STR19## R⁷ is independently selected from: a) hydrogen,

b) C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₁ -C₆ perfluoroalkyl,F, Cl, R¹⁰ O--, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰C(O)--, R¹⁰ OC(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and

c) C₁ -C₆ alkyl substituted by C₁ -C₆ perfluoroalkyl, R¹⁰ O--, R¹⁰C(O)NR¹⁰ --, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, --N(R¹⁰)₂, orR¹¹ OC(O)NR¹⁰ --;

R⁸ is selected from:

a) hydrogen,

b) C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₁ -C₆ perfluoroalkyl, F, Cl, R¹⁰O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰C(O)--, R¹⁰ OC(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and

c) C₁ -C₆ alkyl unsubstituted or substituted by C₁ -C₆ perfluoroalkyl,F, Cl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, (R¹⁰)₂N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --;

R¹⁰ is independently selected from hydrogen, C₁ -C₆ alkyl, benzyl andaryl;

R¹¹ is independently selected from C₁ -C₆ alkyl and aryl;

A¹ and A² are independently selected from: a bond, --CH═CH--,--C.tbd.C--, --C(O)--, --C(O)NR¹⁰ --, O, --N(R¹⁰)--, or S(O)_(m) ;

V is selected from:

a) hydrogen,

b) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl,thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl,isoquinolinyl, and thienyl,

c) aryl,

d) C₁ -C₂₀ alkyl wherein from 0 to 4 carbon atoms are replaced with a aheteroatom selected from O, S, and N, and e) C₂ -C₂₀ alkenyl, and

provided that V is not hydrogen if A¹ is S(O)_(m) and V is not hydrogenif A¹ is a bond, n is 0 and A² is S(O)_(m) ;

W is a heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl,thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, orisoquinolinyl;

Z is independently H₂ or O;

m is 0, 1 or 2;

n is 0, 1, 2, 3 or 4;

p is 0, 1, 2, 3 or 4;

q is 0, 1 or 2;

r is 0 to 5, provided that r is 0 when V is hydrogen; and

u is 0 or 1;

or the pharmaceutically acceptable salts thereof.

The preferred compounds of this invention are as follows:

N-(1(S)-carboxy-3-methylthiopropyl)-3-(4-imidazolylmethyl)aminomethylbenzamide

N-(1(S)-carbomethoxy-3-methylthiopropyl)-3-(4-imidazolylmethyl)aminomethylbenzamide

N-(1(S)-carboxy-3-methylthiopropyl)-3-[N,N-bis-(4-imidazolemethyl)aminomethyl]benzamide

N-(1(S)-carbomethoxy-3-methylthiopropyl)-3-[N,N-bis-(4-imidazolemethyl)aminomethyl]benzamide

N-(1(S)-carboxy-3-methylthiopropyl)3-[(4-imidazolylmethyl)-N-methylaminomethyl]benzamide

N-(1(S)-carbomethoxy-3-methylthiopropyl)3-[(4-imidazolylmethyl)-N-methylaminomethyl]benzamide

N-(1(S)-carboxy-3-methylthiopropyl)4-[(4-imidazolylmethyl)amino]benzamide

N-(1(S)-carbomethoxy-3-methylthiopropyl)4-[(4-imidazolylmethyl)amino]benzamide

N-(1(S)-carboxy-3-methylthiopropyl)-3-[(4-imidazolylmethyl)amino]benzamide

N-(1(S)-carbomethoxy-3-methylthiopropyl)-3-[(4-imidazolylmethyl)amino]benzamide

N-(1(S)-carbomethoxy-3-methylthiopropyl)-3-[(4-imidazolylpropyl)amino]benzamide

N-(1(S)-Carboxy-3-methylthiopropyl)-3-[(4-imidazolylpropyl)amino]benzamide

N-(1(S)-Carbomethoxy-3-methylthiopropyl)-3-[N-(4-imidazolylymethyl)-N-(4-nitrobenzyl)aminomethyl]benzamide

N-(1(S)--Carboxy-3-methylthiopropyl)-3-[N-(4-imidazolylymethyl)-N-(4-nitrobenzyl)aminomethyl]benzamide

N-(1(S)-carboxy-3-methylthiopropyl)-3-[N ,N-bis-(4-nitrophenylmethyl)]aminomethylbenzamide

N-(1(S)-carbomethoxy-3-methylthiopropyl)-3-[N,N-bis-(4-nitrophenylmethyl)aminomethyl]benzamide

or the pharmaceutically acceptable salts thereof.

Specific examples of the compounds of the invention are: ##STR20## orthe pharmaceutically acceptable salts thereof.

In the present invention, the amino acids which are disclosed areidentified both by conventional 3 letter and single letter abbreviationsas indicated below:

    ______________________________________                                        Alanine            Ala        A                                               Arginine           Arg        R                                               Asparagine         Asn        N                                               Aspartic acid      Asp        D                                               Asparagine or      Asx        B                                               Aspartic acid                                                                 Cysteine           Cys        C                                               Glutamine          Gln        Q                                               Glutamic acid      Glu        E                                               Glutamine or       Glx        Z                                               Glutamic acid                                                                 Glycine            Gly        G                                               Histidine          His        H                                               Isoleucine         Ile        I                                               Leucine            Leu        L                                               Lysine             Lys        K                                               Methionine         Met        M                                               Phenylalanine      Phe        F                                               Proline            Pro        P                                               Serine             Ser        S                                               Threonine          Thr        T                                               Tryptophan         Trp        W                                               Tyrosine           Tyr        Y                                               Valine             Val        V                                               ______________________________________                                    

The compounds of the present invention may have asymmetric centers andoccur as racemates, racemic mixtures, and as individual diastereomers,with all possible isomers, including optical isomers, being included inthe present invention.

As used herein, "alkyl" is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms.

As used herein, "cycloalkyl" is intended to include non-aromatic cyclichydrocarbon groups having the specified number of carbon atoms. Examplesof cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and the like.

"Alkenyl" groups include those groups having the specified number ofcarbon atoms and having one or several double bonds. Examples of alkenylgroups include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl,cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, 1-propenyl,2-butenyl, 2-methyl-2-butenyl, isoprenyl, farnesyl, geranyl,geranylgeranyl and the like.

As used herein, "aryl" is intended to include any stable monocyclic,bicyclic or tricyclic carbon ring(s) of up to 7 members in each ring,wherein at least one ring is aromatic. Examples of aryl groups includephenyl, naphthyl, anthracenyl, biphenyl, tetrahydronaphthyl, indanyl,phenanthrenyl and the like.

The term heterocycle or heterocyclic, as used herein, represents astable 5- to 7-membered monocyclic or stable 8- to 11-membered bicyclicor stable 11-15 membered tricyclic heterocycle ring which is eithersaturated or unsaturated, and which consists of carbon atoms and fromone to four heteroatoms selected from the group consisting of N, O, andS, and including any bicyclic group in which any of the above-definedheterocyclic rings is fused to a benzene ring. The heterocyclic ring maybe attached at any heteroatom or carbon atom which results in thecreation of a stable structure. Examples of such heterocyclic elementsinclude, but are not limited to, azepinyl, benzimidazolyl,benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl,benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl,cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl,dihydrobenzothiopyranyl, dihydrobenzothio-pyranyl sulfone, furyl,imidazolidinyl, imidazolinyl, imidazolyl, indolinyl, indolyl,isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl,isothiazolyl, isothiazolidinyl, morpholinyl, naphthyridinyl,oxadiazolyl, 2-oxoazepinyl, 2-oxopiperazinyl, 2-oxopiperidinyl,2-oxopyrrolidinyl, piperidyl, piperazinyl, pyridyl, pyridyl N-oxide,pyridonyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyrimidinyl,pyrrolidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinolinyl N-oxide,quinoxalinyl, tetrahydrofuryl, tetrahydroisoquinolinyl,tetrahydro-quinolinyl, thiamorpholinyl, thiamorpholinyl sulfoxide,thiazolyl, thiazolinyl, thienofuryl, thienothienyl, and thienyl.

As used herein, the terms "substituted aryl", "substituted heterocycle"and "substituted cycloalkyl" are intended to include the cyclic groupwhich is substituted with 1 or 2 substitutents selected from the groupwhich includes but is not limited to F, Cl, Br, CF₃, NH₂, N(C₁ -C₆alkyl₂, NO₂, CN, (C₁ -C₆ alkyl)O--, --OH, (C₁ -C₆ alkyl)S(O)_(m) --, (C₁-C₆ alkyl)C(O)NH--, H₂ N--C(NH)--, (C₁ -C₆ alkyl)C(O)--, (C₁ -C₆alkyl)OC(O)--, N₃, (C₁ -C₆ alkyl)OC(O)NH-- and C₁ -C₂₀ alkyl. WhenR^(3a) and R^(3b) are combined to form --(CH₂)_(s) --, cyclic moietiesare formed. Examples of such cyclic moieties include, but are notlimited to: ##STR21##

In addition, such cyclic moieties may optionally include aheteroatom(s). Examples of such heteroatom-containing cyclic moietiesinclude, but are not limited to: ##STR22##

The pharmaceutically acceptable salts of the compounds of this inventioninclude the conventional non-toxic salts of the compounds of thisinvention as formed, e.g., from non-toxic inorganic or organic acids.For example, such conventional non-toxic salts include those derivedfrom inorganic acids such as hydrochloric, hydrobromic, sulfuric,sulfamic, phosphoric, nitric and the like: and the salts prepared fromorganic acids such as acetic, propionic, succinic, glycolic, stearic,lactic, malic, tartaric, citric, ascorbic, pamoic, maleic,hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic,2-acetoxy-benzoic, fumaric, toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, isethionic, trifluoroacetic and the like.

It is intended that the definition of any substituent or variable (e.g.,R¹⁰, Z, n, etc.) at a particular location in a molecule be independentof its definitions elsewhere in that molecule. Thus, --N(R¹⁰)₂represents --NHH, --NHCH₃, --NHC₂ H₅, etc. It is understood thatsubstituents and substitution patterns on the compounds of the instantinvention can be selected by one of ordinary skill in the art to providecompounds that are chemically stable and that can be readily synthesizedby techniques known in the art as well as those methods set forth below.

The pharmaceutically acceptable salts of the compounds of this inventioncan be synthesized from the compounds of this invention which contain abasic moiety by conventional chemical methods. Generally, the salts areprepared by reacting the free base with stoichiometric amounts or withan excess of the desired salt-forming inorganic or organic acid in asuitable solvent or various combinations of solvents.

The compounds of the invention can be synthesized from their constituentamino acids by conventional peptide synthesis techniques, and theadditional methods described below. Standard methods of peptidesynthesis are disclosed, for example, in the following works: Schroederet at., "The Peptides", Vol. I, Academic Press 1965, or Bodanszky etat., "Peptide Synthesis", Interscience Publishers, 1966, or McOmie (ed.)"Protective Groups in Organic Chemistry", Plenum Press, 1973, or Baranyet al., "The Peptides: Analysis, Synthesis, Biology" 2, Chapter 1,Academic Press, 1980, or Stewart et al., "Solid Phase PeptideSynthesis", Second Edition, Pierce Chemical Company, 1984. The teachingsof these works are hereby incorporated by reference.

Abbreviations used in the description of the chemistry and in theExamples that follow are:

    ______________________________________                                        Ac.sub.2 O Acetic anhydride;                                                  Boc        t-Butoxycarbonyl;                                                  DBU        1,8-diazabicyclo[5.4.0]undec-7-ene;                                DMAP       4-Dimethylaminopyridine;                                           DME        1,2-Dimethoxyethane;                                               DMF        Dimethylformamide;                                                 EDC        1-(3-dimethylaminopropyl)-3-ethyl-                                            carbodiimidehydrochloride;                                         HOBT       1-Hydroxybenzotriazole hydrate;                                    Et.sub.3 N Triethylamine;                                                     EtOAc      Ethyl acetate;                                                     FAB        Fast atom bombardment;                                             HOOBT      3-Hydroxy-1,2,2-benzotriazin-4(3H)-one;                            HPLC       High-performance liquid chromatography;                            MCPBA      m-Chloroperoxybenzoic acid;                                        MsCl       Methanesulfonyl chloride;                                          NaHMDS     Sodium bis(trimethylsilyl)amide;                                   Py         Pyridine;                                                          TFA        Trifluoroacetic acid;                                              THF        Tetrahydrofuran.                                                   ______________________________________                                    

Compounds of this invention are prepared by employing the reactionsshown in the following Reaction Schemes A-J, in addition to otherstandard manipulations such as ester hydrolysis, cleavage of protectinggroups, etc., as may be known in the literature or exemplified in theexperimental procedures. Some key bond-forming and peptide modifyingreactions are:

Reaction A Amide bond formation and subsequenmt generation of the aminomethyl moiety using standard solution or solid phase methodologies.

Reaction B Preparation of a reduced peptide subunit by reductivealkylation of an amine by an aldehyde using sodium cyanoborohydride orother reducing agents.

Reaction C Alkylation of the amino moiety of the central phenyl ring.

Reaction D Peptide bond formation and protecting group cleavage usingstandard solution or solid phase methodologies.

These reactions may be employed in a linear sequence to provide thecompounds of the invention or they may be used to synthesize fragmentswhich are subsequently joined by the alkylation reactions described inthe Reaction Schemes. ##STR23## where X^(L) is a leaving group, e.g.,Br--, I-- or MsO--;.

Reaction Schemes E-M illustrate reactions wherein thenon-sulfhydryl-containing moiety at the N-terminus of the compounds ofthe instant invention is attached to an aminomethylbenzamide subunitwhich may be further elaborated to provide the instant compounds.Thesereactions may be employed in a linear sequence to provide the compoundsof the invention or they may be used to synthesize fragments which aresubsequently joined by the reactions described in Reaction Schemes A-D.

The intermediates whose synthesis are illustrated in Reaction SchemesA-D can be reductively alkylated with a variety of aldehydes, such as I,as shown in Reaction Scheme E. The aldehydes can be prepared by standardprocedures, such as that described by O. P. Goel, U. Krolls, M. Stierand S. Kesten in Organic Syntheses, 1988, 67, 69-75, from theappropriate amino acid (Reaction Scheme E). The reductive alkylation canbe accomplished at pH 5-7 with a variety of reducing agents, such assodium triacetoxyborohydride or sodium cyanoborohydride in a solventsuch as dichloroethane, methanol or dimethylformamide. The product IIcan be deprotected to give the final compounds III with trifluoroaceticacid in methylene chloride. The final product Ill is isolated in thesalt form, for example, as a trifluoroacetate, hydrochloride or acetatesalt, among others. The product diamine III can further be selectivelyprotected to obtain IV, which can subsequently be reductively alkylatedwith a second aldehyde to obtain V. Removal of the protecting group, andconversion to cyclized products such as the dihydroimidazole VII can beaccomplished by literature procedures.

Alternatively, the aminomethylbenzamide subunit can be reductivelyalkylated with other aldehydes such as 1-trityl-4-carboxaldehyde or1-trityl-4-imidazolylacetaldehyde, to give products such as VIII(Reaction Scheme F). The trityl protecting group can be removed fromVIII to give IX, or alternatively, VIII can first be treated with analkyl halide then subsequently deprotected to give the alkylatedimidazole X. Alternatively, the aminomethylbenzamide subunit can beacylated or sulfonylated by standard techniques.

The imidazole acetic acid XI can be converted to the acetate XIII bystandard procedures, and XIII can be first reacted with an alkyl halide,then treated with refluxing methanol to provide the regiospecificallyalkylated imidazole acetic acid ester XIV. Hydrolysis and reaction withthe aminomethylbenzamide subunit in the presence of condensing reagentssuch as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) leads toacylated products such as XV.

If the aminomethylbenzamide subunit is reductively alkylated with analdehyde which also has a protected hydroxyl group, such as XVI inReaction Scheme H, the protecting groups can be subsequently removed tounmask the hydroxyl group (Reaction Schemes H, I). The alcohol can beoxidized under standard conditions to e.g. an aidehyde, which can thenbe reacted with a variety of organometallic reagents such as Grignardreagents, to obtain secondary alcohols such as XX. In addition, thefully deprotected amino alcohol XXI can be reductively alkylated (underconditions described previously) with a variety of aldehydes to obtainsecondary amines, such as XXII (Reaction Scheme J), or tertiary amines.

The Boc protected amino alcohol XVIII can also be utilized to synthesize2-aziridinylmethylpiperazines such as XXIII (Reaction Scheme K).Treating XVIII with 1,1'-sulfonyldiimidazole and sodium hydride in asolvent such as dimethylformamide led to the formation of aziridineXXIII. The aziridine reacted in the presence of a nucleophile, such as athiol, in the presence of base to yield the ring-opened product XXIV.

In addition, the aminomethylbenzamide subunit can be reacted withaldehydes derived from amino acids such as O-alkylated tyrosines,according to standard procedures, to obtain compounds such as XXX, asshown in Reaction Scheme L. When R' is an aryl group, XXX can first behydrogenated to unmask the phenol, and the amine group deprotected withacid to produce XXXI. Alternatively, the amine protecting group in XXXcan be removed, and O-alkylated phenolic amines such as XXXII produced.

Reaction Scheme M illustrates a one pot synthesis of an instant compoundwherein the N-terminus nitrogen is substituted with two differentnon-sulfhydryl-containing moieties. Thus, the aminomethylbenzamidesubunit is treated with one equivalent of an appropriate aldehydea and,after the reductive adduct has been formed, the in situ intermediate istreated with an equivalent of a different aidehyde.

Similar procedures as are illustrated in Reaction Schemes EM may beemployed using other intermediates such as those whose synthesis isillustrated in Reaction Schemes B-D. ##STR24##

The --NR⁴ R⁵ moiety of the compounds of the instant invention mayprovide advantages over a cysteinyl moiety that is incorporated in othertypes of molecules that are known to be inhibitors of farnesyl proteintransferase. In particular, modification of the benzodiazepine compoundsdescribed in published PCT application WO 94/26723 with the such --NR⁴R⁵ substituents as described herein will provide inhibitors of farnesylprotein transferase of the following formulae A and B: ##STR25## whereinthe substituents R, R' and R²⁵ are as defined in WO 94/26723, R^(4benz),R^(4'benz), R^(7benz) and W^(benz) are R⁴, R^(4'), R⁷ and W respectivelyas defined in WO 94/26723 and R^(a) and R^(b) are defined as R⁴ and R5are defined herein respectively.

Preferably,the following combinations of R^(a) and R^(b) are selectedfor incorporation into the compounds of formulae A and B:

    ______________________________________                                        R.sup.a            R.sup.b                                                    ______________________________________                                        imidazol-4-ylacetyl                                                                              H                                                          imidazol-4-ylmethyl                                                                              imidazol-4-ylmethyl                                        4-nitrobenzyl      imidazol-4-ylmethyl                                        3-(4-cyanobenzyl)-imidazol-4-                                                                    H                                                          acetyl                                                                        3-(4-cyanobenzyl)-imidazol-4-                                                                    CH.sub.3                                                   acetyl                                                                        ______________________________________                                    

Most preferably, the benzodiazepine compound would be selected from thefollowing formulae: ##STR26## wherein R and R' are as defined in WO94/26723 and W^('benz) is W' as defined in WO 94/26723 and R^(a) andR^(b) are defined as R⁴ and R⁵ are defined herein respectively.

Such benzodiazepine analogs may be synthesized by techniques well knownin the art, as well as procedures outlined in WO 94/26723. Generalmethods of synthesis of the benzediazapine analogs of this invention areshown in Schemes N, P and Q. Typically a convergent route is employed,which joins the key intermediate 9 (Scheme N) with suitablyfunctionalized amine and R^(a) and R^(b) components (Schemes P and Q)using standard amide bond-forming procedures.

As shown in Scheme N, the protected amino acid 9 may be prepared from asuitably substituted 2-aminobenzophenone (1). Many 2-aminobenzophenonesare known in the art or are available form commercial sources such asAldrich Chemical Co. General methods for the synthesis of new2-aminobenzophenones may be found in the literature (c.f. Walsh, D. A.Synthesis, 677-688 (1980).

Acylation of 1 with a haloacetyl halide, such as bromoacetyl bromide ina suitable solvent mixture, such as water/CH₂ Cl₂, typically attemperatures ranging from 0° C. to 24° C., produces amide 2. Reaction of2 with ammonia in a polar solvent such as methanol at 25° to 75° C. thengives the 1,4-benzodiazepin-2-one 3, after evaporation of the solvent.Alkylation of 3 with a substituted organic ester (4), preferablytert-butyl bromacetate, in the presence of a base, preferably Cs₂ CO₃ in1-methyl-2-pyrrolidinone at ambient temperature, gives 5. Alternatively,3 may be alkylated at N-1 with a variety of other alkylating agents, forinstance, esters of substituted or unsubstituted acrylates,4-bromobutanoates, etc. Branched compounds (i.e. R^(4benz) and/orR^(4'benz) ≠H), may be prepared by generation of the polyanion of 5 withbase and alkylation with an appropriate alkyl halide. Subsequent toalkylation, the ester of 5 may be cleaved with an acid such as TFA (forthe tert-butyl esters) or under mild aqueous base hydrolysis (for otheralkyl esters) at temperatures between 0° and 25 ° C.

The acid 6 is converted to amino acid 8 via reaction of the dianion,generated with at least two equivalents of a strong base with anelectrophilic aminating agent. Alternatively, 6 may be halogenated andreacted with an amine source such as azide (followed by reduction) orammonia. Preferably, 6 is reacted with 4 equivalents of potassiumtert-butoxide in glyme at -5 ° C. for 30 min and treated with 1.1equivalents of isobutyl nitrite. The resulting oxime 7 can then bereduced to the racemic amino acid 8 using a variety of reductants,preferably hydrogenation at 40 psig in the presence of Ruthenium oncarbon or Raney nickel in methanol at 50° to 70 ° C. for 1-4 days.

Amino acid 8 is then suitably protected for selective coupling at thecarboxyl terminus. For example, 8 can be converted to the N-BOCderivative 9 using standard amino acid protection conditions,preferably, reaction with equimolar amounts of di-tert-butyl dicarbonateand triethyl amine in DMF/water at ambient temperature.

For compounds where R^(a) ≠H, 9 can be alkylated at nitrogen with a widevariety of alkylating agents including n-alkyl, branched alkyl, andbenzyl, according to the standard procedure of Benoiton, et al., Can. J.Chem. 1977, 55, 906. For example, reaction of 9 with at least 2equivalents of base and an alkylating agent in a polar, aprotic solventat 0° to 50 ° C. for 0.5 to 48 h give 10. Also, the reactions shown inSchemes E-M may be utilized with the compound 9. ##STR27##

Compounds 9 and 10 can be further elaborated according to Schemes P. Ingeneral, the carboxylic acid function of 9 and 10 is reacted with asuitably protected amine component using standard solid phase (Scheme P)or solution phase peptide synthesis procedures. The BOC or otherprotecting group of N-3 of the benzodiazepinone is removed and the aminefunction then coupled with a third component, for example, a suitablyprotected amino acid, and then deprotected, again employing standardprocedures. The resulting product is subsequently purified bychromatography or crystallization. ##STR28##

Alternatively, 3 may be directly alkylated with the "top" sidechain inone intact piece, as shown in Scheme Q. Reaction of 3 with an alkylhalide such as a suitably substituted benzyl bromide, alkyl bromide, inthe presence of a base, preferably NaH or Cs₂ CO₃, gives 11, which maybe processed according to the reactions illustrated in Scheme I toprovide the desired FPTase inhibitors. ##STR29## wherein P.G. is asuitably selected protecting group which is utilized if necessary.

The compounds of this invention inhibit Ras farnesyl transferase whichcatalyzes the first step in the post-translational processing of Ras andthe biosynthesis of functional Ras protein. These compounds are usefulas pharmaceutical agents for mammals, especially for humans. Thesecompounds may be administered to patients for use in the treatment ofcancer. Examples of the type of cancer which may be treated with thecompounds of this invention include, but are not limited to, colorectalcarcinoma, exocrine pancreatic carcinoma, and myeloid leukemias.

The compounds of this invention may be administered to mammals,preferably humans, either alone or, preferably, in combination withpharmaceutically acceptable carriers or diluents, optionally with knownadjuvants, such as alum, in a pharmaceutical composition, according tostandard pharmaceutical practice. The compounds can be administeredorally or parenterally, including the intravenous, intramuscular,intraperitoneal, subcutaneous, rectal and topical routes ofadministration.

For oral use of a chemotherapeutic compound according to this invention,the selected compound may be administered, for example, in the form oftablets or capsules, or as an aqueous solution or suspension. In thecase of tablets for oral use, carriers which are commonly used includelactose and corn starch, and lubricating agents, such as magnesiumstearate, are commonly added. For oral administration in capsule form,useful diluents include lactose and dried corn starch. When aqueoussuspensions are required for oral use, the active ingredient is combinedwith emulsifying and suspending agents. If desired, certain sweeteningand/or flavoring agents may be added. For intramuscular,intraperitoneal, subcutaneous and intravenous use, sterile solutions ofthe active ingredient are usually prepared, and the pH of the solutionsshould be suitably adjusted and buffered. For intravenous use, the totalconcentration of solutes should be controlled in order to render thepreparation isotonic.

The present invention also encompasses a pharmaceutical compositionuseful in the treatment of cancer, comprising the administration of atherapeutically effective amount of the compounds of this invention,with or without pharmaceutically acceptable carriers or diluents.Suitable compositions of this invention include aqueous solutionscomprising compounds of this invention and pharmacologically acceptablecarriers, e.g., saline, at a pH level, e.g., 7.4. The solutions may beintroduced into a patient's intramuscular blood-stream by local bolusinjection.

When a compound according to this invention is administered into a humansubject, the daily dosage will normally be determined by the prescribingphysician with the dosage generally varying according to the age,weight, and response of the individual patient, as well as the severityof the patient's symptoms.

In one exemplary application, a suitable amount of compound isadministered to a mammal undergoing treatment for cancer. Administrationoccurs in an amount between about 0.1 mg/kg of body weight to about 20mg/kg of body weight per day, preferably of between 0.5 mg/kg of bodyweight to about 10 mg/kg of body weight per day.

The compounds of the instant invention are also useful as a component inan assay to rapidly determine the presence and quantity offarnesyl-protein transferase (FPTase) in a composition. Thus thecomposition to be tested may be divided and the two portions contactedwith mixtures which comprise a known substrate of FPTase (for example atetrapeptide having a cysteine at the amine terminus) and famesylpyrophosphate and, in one of the mixtures, a compound of the instantinvention. After the assay mixtures are incubated for an sufficientperiod of time, well known in the art, to allow the FPTase tofarnesylate the substrate, the chemical content of the assay mixturesmay be determined by well known immunological, radiochemical orchromatographic techniques. Because the compounds of the instantinvention are selective inhibitors of FPTase, absence or quantitativereduction of the amount of substrate in the assay mixture without thecompound of the instant invention relative to the presence of theunchanged substrate in the assay containing the instant compound isindicative of the presence of FPTase in the composition to be tested.

It would be readily apparent to one of ordinary skill in the art thatsuch an assay as described above would be useful in identifying tissuesamples which contain farnesyl-protein transferase and quantitating theenzyme. Thus, potent inhibitor compounds of the instant invention may beused in an active site titration assay to determine the quantity ofenzyme in the sample. A series of samples composed of aliquots of atissue extract containing an unknown amount of farnesyl-proteintransferase, an excess amount of a known substrate of FPTase (forexample a tetrapeptide having a cysteine at the amine terminus) andfarnesyl pyrophosphate are incubated for an appropriate period of timein the presence of varying concentrations of a compound of the instantinvention. The concentration of a sufficiently potent inhibitor (i.e.,one that has a Ki substantially smaller than the concentration of enzymein the assay vessel) required to inhibit the enzymatic activity of thesample by 50% is approximately equal to half of the concentration of theenzyme in that particular sample.

EXAMPLES

Examples provided are intended to assist in a further understanding ofthe invention. Particular materials employed, species and conditions areintended to be further illustrative of the invention and not limitativeof the reasonable scope thereof.

The standard workup referred to in the examples refers to solventextraction and washing the organic solution with 10% citric acid, 10%sodium bicarbonate and brine as appropriate. Solutions were dried oversodium sulfate and evaporated in vacuo on a rotary evaporator.

Example 1

N-(1(S)-carboxy-3-methylthiopropyl)-3-(4-imidazolylmethyl)aminomethylbenzamidedihydrochloride

Step A: Preparation ofN-(1(S)-carbomethoxy-3-methylthiopropyl)-3-chloromethylbenzamide

To a solution of (S) methionine methyl ester hydrochloride (10.56 g,52.9 mmol) and 4-N-methylmorpholine (21.34 g, 211.6 mmol) under nitrogenin 200 mL of methylene chloride at 0° C. was added 3-chloro-methylbenzoyl chloride (10.00 g, 52.9 mmol) dropwise via syringe. Afteraddition the cooling bath was removed and the resulting solution wasstirred for 16 h at 20° C. The methylene chloride solution was extractedwith 125 mL each of water, 2% potassium hydrogen sulfate, saturatedsodium hydrogen carbonate, and saturated sodium chloride. The methylenechloride was dried over magnesium sulfate and concentrated in vacuo tothe title compound as an oil. ¹ HNMR (300 MHz, CDCl₃)δ 7.85 (1H, s),7.76 (1H, d, J=8 Hz), 7.56 (1H, d, J=8 Hz), 7.45 (1H, t, J=8 Hz), 6.96(1H, d, J=7 Hz), 4.94 (1H, q, J=5 Hz), 4.62 (2H, s), 3.81 (3H, s), 2.60(2H, t, J=8 Hz), 2.30 (1H, m), 2.15 (1H, m), 2.12 (3H, s).

Step B: Preparation ofN-(1(S)-carbomethoxy-3-methylthiopropyl)-3-azidomethylbenzamide

To a stirred solution of the product from Step A (13.52 g, 42.80 mmol)in 50 mL of dimethylsulfoxide under nitrogen was added lithium azide(2.3 g, 47.10 mmol). The solution was stirred for 2 h The reactionmixture was then partitioned with 300 mL of ethyl acetate and 200 mL ofwater. The ethyl acetate layer was washed with 125 mL of saturatedsodium chloride, dried over magnesium sulfate and concentrated in vacuoto afford the title compound as an oil. ¹ HNMR (300 MHz, CDCl₃)δ 7.75(2H, m), 7.47 (2H, m), 7.02 (1H, d, J=8 Hz), 4.94 (1H, q, J=5 Hz), 4.41(2H, s), 3.80 (3H, s), 2.60 (2H, t, J=6 Hz), 2.30 (1H, m), 2.15 (1H,m),2.11 (3H, s).

Step C: Preparation ofN-(1(S)-carbomethoxy-3-methylthiopropyl)-3-aminomethylbenzamide

To a solution of the product from Step B (11.8 g, 35.08 mmol) in 150 mLof methanol under nitrogen was added 1.5 g 10% palladium on carbon.Hydrogen was applied to the mixture at 1 atmosphere for 1.5 h. Thereaction mixture was filtered and concentrated in vacuo to obtain 10.3 g(34.76 mmol) of crude product as an oil. The crude product waschromatographed on 500 g of silica gel with chloroform/methanol 95/5 aseluant to afford the title compound as an oil. ¹ HNMR (300 MHz, CDCl₃)δ7.78 (1H, s), 7.68 (1H, d, J=7 Hz), 7.47 (1H, d, J=7 Hz), 7.40 (1H, t,J=8 Hz), 7.02 (1H, d, J=7 Hz), 4.93 (1H, q, J=5 Hz), 3.92 (2H, s), 3.79(3H, s), 2.59 (2H, t, J=8 Hz), 2.24 (1H, m), 2.12 (1H, m), 2.10 (3H, s),1.85 (2H,s).

Step D: Preparation of N-(1(S)-carbomethoxy-3-methylthiopropyl)3-[(1-triphenylmethyl)-4-imidazolylmethyl]aminomethyl benzamide

To a solution of the product from Step C (0.228 g, 0.767 mmol) in 10 mLof 1,2-dichloroethane was added glacial acetic acid dropwise until a pH5.5 was achieved. To this mixture at 20° C. was added 0.5 g of crushed 4Å molecular sieves, sodium triacetoxyborohydride (0.487 g, 2.30 mmol),and 1-(triphenylmethyl)-4imidazole carboxaldehyde (0.130 g, 0.384 mmol).The resulting solution was stirred for 12-72 h. The reaction mixture wasfiltered through celite and partitioned with 125 mL of water and 150 mLof ethyl acetate. The ethyl acetate layer was washed with 125 mL each ofsaturated sodium hydrogen carbonate and saturated sodium chloride, driedover magnesium sulfate, and concentrated in vacuo to yield 0.363 g ofcrude product. The crude product was chromatographed on silica geleluting with chloroform/methanol 95/5 to afford the title compound. ¹HNMR (300 MHz, CDCl₃)δ 7.83 (1H, s), 7.71 (1H, d, J=7 Hz), 7.40 (4H, m),7.32 (8H, m), 7.25 (1H, s), 7.12 (7H, m), 6.71 (1H, s), 4.93 (1H, q, J=5Hz), 3.85 (2H, s), 3.77 (3H, s), 3.71 (2H, s), 2.58 (2H, t, J=8 Hz),2.25 (1H, m), 2.10 (1H, m), 2.09 (3H, s).

Step E. Preparation ofN-(1(S)-carbomethoxy-3-methylthiopropyl)-3-(4-imidazolylmethyl)aminomethylbenzamidedihydrochloride

To a solution of the product from Step D (0.220 g, 0.356 mmol) in 10 mLof methylene chloride was added triethylsilane (0.165 g, 1.42 mmol) and5 mL of trifluoroacetic acid. The solution was stirred for 45 min,evaporated in vacuo, and partitioned with hexane and 0.1%trifluoroacetic acid in water:methanol 2:1. The 0.1% trifluoroaceticacid/water-methanol solution was injected directly onto a Delta-Pak(C-18, 100 Å, 15 mm, 40 mm×100 mm) prep HPLC column. The gradient at 40mL/min. was 100% 0.1% TFA/water for 5 min. followed by 95% 0.1%TFA/water :5% 0.1% TFA/acetonitrile to 70% 0.1% TFA/water:30.% 0.1%TFA/acetonitrile over a period of 40 min. The pure fractions werepooled, evaporated in vacuo to near dryness, and then taken up in 5 mLof water. This water solution was passed through a 1.2 gm. column ofBio-Rad AG 3-X4 chloride anion exchange resin. The resulting aqueouscolumn eluant was lyophillized overnight to yield the title compound asa solid. ¹ HNMR (300 MHz, CD₃ OD)δ 9.04 (1H, s), 8.06 (1H, s), 7.96 (1H,d, J=8 Hz), 7.83 (1H, s), 7.76 (1H, d, J=8 Hz), 7.63 (1H, t, J=8 Hz),4.81 (1H, q, J=5 Hz), 4.52 (2H, s), 4.42 (2H, s), 3.77 (3H, s), 2.63(2H, m), 2.22 (1H, m), 2.16 (1H, m), 2.13 (3H, s). FAB mass spectrum m/e377 (m+1).

Analysis calculated for C₁₈ H₂₄ N₄ O₃ S•3.3 HCl: C, 43.57; H, 5.55; N,11.29. Found: C, 43.56; H, 5.54; N, 11.82.

Step F: Preparation ofN-(1(S)-carboxy-3-methylthiopropyl)-3-(4-imidazolylmethyl)aminomethylbenzamide dihydrochloride

The product from Step E (0.030 g, 0.067 mmol) was dissolved in 5 mL ofmethanol and 3 mL of 5% sodium hydroxide and stirred for 1 h undernitrogen. The reaction mixture was injected directly onto a preparativereverse phase HPLC column with conditions identical as in thepreparation of the compound in Step E. Pure fractions were pooled,evaporated in vacuo, and the sample was converted to the hydrochloridesalt as before. Lyophillization overnight afforded 0.022 g (0.051 mmol)of the title compound as a solid. ¹ HNMR (300 MHz, CD₃ OD)δ 9.06 (1H,s), 8.06 (1H, s), 7.96 (1H, d, J=8 Hz), 7.83 (1H, s), 7.76 (1H, d, J=8Hz), 7.61 (1 H, t, J=8 Hz), 4.78 (1H, q, J=5 Hz), 4.53 (2H, s), 4.47(2H, s), 2.63 (2H, m), 2.25 (1H, m), 2.15 (1H, m), 2.13 (3H, s). FABmass spectrum m/e 363 (m+1).

Analysis calculated for C₇ H₂₂ N₄ O₃ S•3.3 HCl•0.5 H₂ O: C,41.57; H,5.40; N, 11.41. Found: C, 41.54; H, 5.42; N, 11.05.

Example 2

N-(1(S)-carboxy-3-methylthiopropyl)-3-[N,N-bis(4-imidazolemethyl)aminomethyl]benzamidedihydrochloride

Step A: Preparation ofN-(1(S)-carbomethoxy-3-methylthiopropyl)-3-[N,N-bis(1-triphenylmethyl)-4-imidazolylmethyl]-aminomethyl-benzamide

To a solution of the product from Example 1, Step C (0.100 g, 0.357mmol) in 10 mL of 1,2-dichloroethane was added glacial acetic aciddropwise until the pH was 5.5. To this mixture at 20° C. was added 0.5 gof crushed 4 Å sieves, sodium triacetoxyborohydride (0.226 g, 2.30mmol), and 1-(triphenylmethyl)-4-imidazole carboxaldehyde (0.130 g, 1.07mmol). The resulting solution was stirred for 12-72 h. The reactionmixture was filtered through celite and partitioned with 125 mL of waterand 150 mL of ethyl acetate. The ethyl acetate layer was washed with 125mL each of saturated sodium hydrogen carbonate and saturated sodiumchloride, dried over magnesium sulfate, and concentrated in vacuo toyield the title compound.

Step B: Preparation ofN-(1(S)-carbomethoxy-3-methylthiopropyl)-3-[N,N-bis(4-imidazolylmethyl)aminomethyl]benzamidedihydrochloride

To a solution of the product from Step A (0.320 g, 0.341 mmol) in 10 mLof methylene chloride was added triethylsilane (0.159 g, 1.36 mmol) and5 mL of trifluoroacetic acid. The solution was stirred for 45 min,evaporated, and partitioned between hexane and 0.1% TFA inwater-methanol 2:1. The 0.1% TFA/water:methanol solution was injecteddirectly onto a Delta-Pak (C-18, 100 Å, 15 mm, 40 mm×100 mm) preparativeHPLC column. The gradient at 40 mL/min was 100% 0.1% TFA/water for 5 minfollowed by 95% 0.1% TFA/water to 60% 0.1% TFA/water :40% 0.1%TFA/acetonitrile over 40 min. The pure fractions were pooled, evaporatedto near dryness, and then taken up in 5 mL of water. The aqueoussolution was passed through a 1.2 gm. column of Bio-Rad AG 3-X4 chlorideanion exchange resin. The resulting aqueous column eluant waslyophillized overnight to yield the title compound as a solid. ¹ HNMR(300 MHz, CD₃ OD)δ 8.92 (2H, s), 7.94 (1H, s), 7.78 (1H, d, J=8 Hz),7.62 (2H, s), 7.58 (1H, d, J=8 Hz), 7.44 (1H, t, J=8 Hz), 4.81 (1H, q,J=5 Hz), 4.06 (4H, s), 3.93 (2H, s), 3.77 (3H, s), 2.63 (2H, m), 2.22(1H, m), 2.16 (1H, m), 2.13 (3H, s ). FAB mass spectrum m/e 457 (m+1).

Analysis calculated for C₂₂ H₂₈ N₆ O₃ S•4.8 HCl•0.2 H₂ O: C, 41.66; H,5.28; N, 13.25. Found: C, 41.62; H, 5.27; N, 13.02

Step C: Preparation ofN-(1(S)-carboxy-3-methylthiopropyl)-3-[N,N-bis(4-imidazolemethyl)aminomethyl]benzamidedihydrochloride

The compound from Step B (0.035 g, 0.052 mmol) was dissolved in 5 mL ofmethanol and 3 mL of 5% sodium hydroxide and stirred for 1 hr undernitrogen. The reaction mixture was injected directly onto a preparativeHPLC column with conditions identical as in Step B. Pure fractions werepooled, evaporated, and the sample converted to the hydrochloride saltas before. Lyophilization overnight afforded the title compound as asolid. ¹ HNMR (300 MHz, CD₃ OD) δ 8.88 (2H, s), 7.87 (1H, s), 7.75 (1H,d, J=8 Hz), 7.55 (1H, s), 7.50 (1H, d, J=8 Hz), 7.42 (1H, t, J=8 Hz),4.78 (1H, q, J=5 Hz), 3.88 (4H, s), 3.77 (2H, s), 2.63 (2H, m), 2.25(1H, m), 2.15 (1H, m), 2.13 (3H, s). FAB mass spectrum m/e 443 (m+1).

Analysis calculated for C₂₁ H₂₆ N₆ O₃ S•5.4 HCl•1.5 H₂ O: C, 37.91; H,5.21; N, 12.63. Found: C, 37.97; H, 5.22; N, 12.37.

Example 3

N-(1(S)-carboxy-3-methylthiopropyl)3-[(4-imidazolylmethyl)-N-methylaminomethyl]benzamide dihydrochloride

Step A: Preparation of Methyl 3-chloromethyl benzoate

To a solution of triethylamine (11.0 mL) in methanol (150 mL) at 0° C.was added 3-chloromethylbenzoyl chloride (5.0 g) dropwise. Afterstirring at 20° C. for 0.5 h the solution was concentrated in vacuo. Theresidue was partitioned with 125 mL of water and 150 mL of ethylacetate. The ethyl acetate layer was washed with 125 mL each ofsaturated sodium hydrogen carbonate, 2% potassium hydrogen sulfate andsaturated sodium chloride, dried over magnesium sulfate, andconcentrated in vacuo to yield the title compound. ¹ HNMR (300 MHz,CDCl₃) δ 8.07 (1H, s), 7.99 (1H, d, J=8 Hz), 7.59 (1H, d, J=8 Hz), 7.43(1H, t, J=8 Hz), 4.62 (2H, s), 3.92 (3H, s).

Step B: Preparation of Methyl 3-azidomethylbenzoate

Starting with the product from Step A the method used in Step B ofExample 1 was used to prepare the title compound.

Step C: Preparation of Methyl 3-aminomethyl benzoate

Starting with the product from Step B the method used in Step C ofExample 1 was used to prepare the title compound.

Step D: Preparation of Methyl 3-(t-butyloxycarbonyl)aminomethyl benzoate

To a solution of the product from Step C (1.14 g) in methylene chloride(50 mL) was added triethylamine (2.90 mL) and di-tert-butyl dicarbonate(1.67 g) and the mixture was stirred 16 h. The solution was partitionedwith water and methylene chloride. The methylene chloride layer waswashed with saturated sodium hydrogen carbonate, 2% potassium hydrogensulfate and saturated sodium chloride, dried over magnesium sulfate, andconcentrated in vacuo to yield 1.71 g of the crude product.Chromotography on silica gel with hexane/ethyl acetate 9/1 yielded thetitle compound. ¹ HNMR (300 MHz, CDCl₃) δ 7.95 (1H, s), 7.93 (1H, d, J=8Hz), 7.49 (1H, d, J=8 Hz), 7.41 (1H, t, J=8 Hz), 4.90 (1H, b), 4.37 (2H,d, J=6 Hz), 3.92 (3H, s), 1.45 (9H, s).

Step E: Preparation of Methyl3-[(t-butyloxycarbonyl)-N-methylaminomethyl]benzoate

To a solution of the product from Step E (1.42 g) in dimethylformamide(30 mL) at 0° C. was added sodium hydride (0.43 g, 60% dispersion inminerol oil). After stirring for 0.5 h methyl iodide (0.40 mL) was addedand the mixture was stirred 16 h at 20° C. The solution was concentratedin vacuo and the residue was partitioned between ethyl acetate andwater. The ethyl acetate layer was washed with saturated sodium hydrogencarbonate, 2% potassium hydrogen sulfate and saturated sodium chloride,dried over magnesium sulfate, and concentrated in vacuo to yield thecrude product. Chromotography on silica gel with hexane/ethyl acetate9/1 yielded 0.35 g of the title compound. ¹ HNMR (300 MHz, CDCl₃) δ 7.93(2H, m), 7.42 (2H, m), 4.45 (2H, s), 3.92 (3H, s), 2.83 (3H, d), 1.47(9H, s).

Step F: Preparation of3-[(t-butyloxycarbonyl)-N-methylaminomethyl]benzoic acid

To a solution of the product from Step E (0.35 g) in methanol was added5% sodium hydroxide. After stirring for 2 h the methanol was evaporatedand the aqueous layer was adjusted to pH 3 with 2% potassium hydrogensulfate. The aqueous layer was extracted with ethyl acetate severaltimes. The ethyl acetate layer was washed with saturated sodiumchloride, dried over magnesium sulfate, and concentrated in vacuo toyield the title compound.

Step G: Preparation of N-(1(S)-carbomethoxy-3-methylthiopropyl)-3-[(t-butyloxycarbonyl)-N-methylaminomethyl]benzamide

To a solution of the product from Step F (0.27 g) in dimethylformamide(10 mL) was added hydroxybenzotriazole (0.16 g), EDC (0.19 g),N-methylmorpholine (0.40 mL), and (S) methione methyl esterhydrochloride (0.203 mg). After stirring for 2 h the solution wasconcentrated in vacuo and the residue was partitioned with water andethyl acetate. The ethyl acetate layer was washed with saturated sodiumhydrogen carbonate, 2% potassium hydrogen sulfate and saturated sodiumchloride, dried over magnesium sulfate, and concentrated in vacuo toyield the title compound. ¹ HNMR (300 MHz, CDCl₃) δ 7.70 (2H, s), 7.40(2H, m), 6.95 (1H, d, J=7 Hz), 4.94 (1H, q, J=7 Hz), 4.45 (2H, s), 3.81(3H, s), 2.82 (3H, d), 2.59 (2H, m), 2.30 (1H, m), 2.13 (1H, m), 2.12(3H, s), 1.46 (9H, s).

Step H: Preparation ofN-(1(S)-carbomethoxy-3-methylthiopropyl)-3-(N-methylaminomethyl)benzamidetrifluoroacetate

To a solution of the product from Step G in methylene chloride was addedtrifluoroacetic acid (33% by volume). After stirring for 1 h thesolution was concentrated in vacuo to yield the title compound.

Step I: Preparation ofN-(1(S)-carbomethoxy-3-methylthiopropyl)-3-[(1-triphenylmethyl)-4-imidazolylmethyl-N-methylaminomethyl]benzamide

Starting with the product from Step H (0.18 g) the method described inStep D of Example 1 was used to prepare the title compound.

Step J: Preparation ofN-(1(S)-carbomethoxy-3-methylthiopropyl)-3-[(4-imidazolylmethyl)-N-methyl-minomethyl]benzamidedihydrochloride

Starting with the compound from Step I (0.24 g) the method described inStep E of Example 1 was used to prepare the title compound. FAB masspectrum m/e 391 (m+1).

Analysis for C₁₉ H₂₆ N₄ O₃ S•5.0 HCl•0.5 H₂ O: Calculated: C, 39.32; H,5.56; N, 9.65; Found: C, 39.33; H, 5.57; N, 9.38.

Step K: Preparation ofN-(1(S)-carboxy-3-methylthiopropyl)-3-[(4-imidazolemethyl)-N-methyl-aminomethyl]benzamidedihydrochloride

Starting with the compound from Step J (0.035 g) the method described inStep F of Example 1 was used to prepare the above title compound. FABmas spectrum m/e 377 (m+1).

Analysis for C₁₈ H₂₄ N₄ O₃ S•3.70 HCl•0.2 H₂ O: Calculated C, 42.05; H,5.51; N, 10.90; Found: C, 42.09; H, 5.49; N, 10.70.

Example 4

N-(1(S)-carboxy-3-methylthiopropyl)4-[(4-imidazolylmethyl)amino]benzamide dihydrochloride

Step A: Preparation of 4-t-butyloxycarbonyl- aminobenzoic acid

Starting with 4-aminobenzoic acid (2.00 g) dissolved in tetrahydrofuran(50 mL) and 5% sodium hydroxide (15 mL) the method described in Step Dof Example 3 was used to prepare the title compound. After extractivework up obtained the title compound. ¹ HNMR (300 MHz, CDCl₃) δ 8.04 (2H,d, J=9 Hz), 7.46 (2H, d, J=9 Hz), 6.75 (1H, s), 1.46 (9H, s).

Step B: Preparation ofN-(1(S)-carbomethoxy-3-methylthiopropyl)-4-(t-butyloxycarbonyl)aminobenzamide

To a solution of the product from Step A (0.5 g) in dimethylformamide(20 mL) was added hydroxybenzotriazole (0.37 g), EDC (0.51 g),N-methylmorpholine 0.8 mL), and (S) methione methyl ester hydrochloride(0.49 g). After stirring for 16 h the solution was concentrated in vacuoand the residue was partitioned with water and ethyl acetate. The ethylacetate layer was washed with saturated sodium hydrogen carbonate, 2%potassium hydrogen sulfate and saturated sodium chloride, dried overmagnesium sulfate, and concentrated in vacuo to yield the titlecompound.

Step C: Preparation ofN-(1(S)-carbomethoxy-3-methylthiopropyl)-4-aminobenzamide

To a solution of the product from Step B in methylene chloride was addedtrifluoroacetic acid (33% by volume). After stirring for 1 h thesolution was concentrated in vacuo to yield the trifluoroacetate salt ofthe product (0.59 g). This product was partioned between ethyl acetateand saturated sodium bicarbonate. The ethyl acetate layer was washedwith saturated sodium chloride, dried over magnesium sulfate, andconcentrated in vacuo to yield the title compound. ¹ HNMR (300 MHz,CDCl₃) δ 7.64 (2H, d, J=8 Hz), 6.75 (1H, d, J=8 Hz), 6.65 (2H, d, J=8Hz), 4.90 (1H, q, J=5 Hz), 3.78 (3H, s), 2.57 (2H, m), 2.27 (1H, m),2.08 (4H, m).

Step D: Preparation ofN-(1(S)-carbomethoxy-3-methylthiopropyl)-4-[(1-triphenylmethyl)-4-imidazolylmethyl]aminobenzamide

Starting with the product from Step C (0.07 g) the method described inStep D of Example 1 was used to prepare the title compound.

Step E: Preparation ofN-(1(S)-carbomethoxy-3-methylthiopropyl)-4-(4-imidazolylmethyl)aminobenzamidedihydrochloride

Starting with the product from Step D (0.24 g) the method described inStep E of Example 1 was used to prepare the title compound. FAB masspectrum m/e 363 (m+1).

Analysis for C₁₇ H₂₂ N₄ O₃ S•2.8 HCl: Calculated: C, 43.99; H, 5.39; N,12.07; Found: C, 43.94; H, 5.37; N, 12.24.

Step F: Preparation ofN-(1(S)-carboxy-3-methylthiopropyl)-4-[(4-imidazolylmethyl)amino]benzamidedihydrochloride

Starting with (5) (0.035 g) the method described in Step F of Example 1was used to prepare the title compound. FAB mas spectrum m/e 349 (m+1).

Analysis for C₁₆ H₂₀ N₄ O₃ S•3.10 HCl•1.2 H₂ O: Calculated: C, 39.91; H,5.13; N, 11.63; Found: C, 39.87; H, 5.12; N, 11.22.

Using the appropriate staffing materials the methods described above forExample 4 were used to prepare Examples 5-7.

Example 5

N-(1(S)-carboxy-3-methylthiopropyl)-3-[(4-imidazolylmethyl)amino]benzamidedihydrochloride

FAB mass spectrum m/e 349 (m+1).

Analysis for C₁₆ H₂₀ N₄ O₃ S•3.2 HCl: Calculated: C, 41.37; H, 5.03; N,12.06; Found: C, 41.32; H, 4.92; N, 11.69.

Example 6

N-(1(S)-carbomethoxy-3-methylthiopropyl)-3-[(4-imidazolylpropyl)amino]benzamidedihydrochloride

FAB mass spectrum m/e 391 (m+1).

Analysis for C₁₉ H₂₆ N₄ O₃ S•2.4 HCl•1.3 H₂ O: Calculated: C, 45.53; H,6.23; N, 11.18; Found: C, 45.51; H, 6.25; N, 11.10.

Example 7

N-(1(S)-Carboxy-3-methylthiopropyl)-3-[(4-imidazolylpropyl)amino]benzamidedihydrochloride

FAB mass spectrum m/e 377 (m+1).

Analysis for C₁₈ H₂₄ N₄ O₃ S•3.0 HCl•0.5 H₂ O: Calculated: C, 43.73; H,5.71; N, 11.33; Found: C, 43.67; H, 5.71; N, 10.72.

Example 8

N-(1(S)-Carboxy-3-methylthiopropyl)-3-[N-(4-imidazolylymethyl)-N-(4nitrobenzyl)aminomethyl]benzamideditrifluoroacetate

Step A:N-(1(S)-Carbomethoxy-3-methylthiopropyl)-3-[N-(4-imidazolylymethyl)-N-(4-nitrobenzyl)aminomethyl]benzamideditrifluoroacetate

N-(1(S)-carbomethoxy-3-methylthiopropyl)-3-aminomethylbenzamide (0.104g, 0.352 mmol) was dissolved in dichloroethane (5 mL). Crushed molecularsieves (0.209 g) and sodium triacetoxyborohydride (0.186 g, 0.881 mmol).The pH was about 7.5. 4-Nitrobenzaldehyde (0.0533 g, 0.352 mmol) wasadded plus 0.5 drop of acetic acid to bring the pH to about 7. Thereaction was stirred 2 h under nitrogen at 20° C.1-Triphenylmethylimidazolyly-4-carboxaldehyde (0.119 g, 0.352 mmol) wasadded to the reaction mixture with additional sodiumtriacetoxyborohydride and dichloroethane (2 mL). Triethylamine (5 drops)brought the pH to about 7. The reaction continued to stir at 20° C.under nitrogen overnight. The reaction was quenched with saturatedsodium bicarbonate solution and let stir 20 min. It was then removed toa separatory funnel with copious amounts of ethyl acetate. The aqueouslayer was removed and the organic phase was washed with saturated brineand dried over magnesium sulfate. The crude product was chromatographedon silica gel with 50% ethyl acetate in hexane. This chromatographedproduct was dissolved in dichloromethane (7 mL); triethylsilane (0.5 mL,3.13 mmol) was added and then trifluoroacetic acid (3.5 mL). After 0.5 hat 20° C., the solvent was evaporated and the residue partitionedbetween hexane and water. The aqueous solution was purified bypreparative reverse phase HPLC using a 100 mm Waters PrepPak® reversephase column (DeltaPak™ C18, 50 μM, 100 Å) and pure product isolated bygradient elution using 80% 0.1% trifluoroacetic acid in water (SolventA) and 20% 0.1% trifluoroacetic acid in acetonitrile (Solvent B) to 55%Solvent A and 45% Solvent B. The pure fractions were combined and thesolvent evaporated, and the pure product was dissolved in water andlyophilized to give the title compound as a clear, pale yellow solid. ¹HNMR (CD₃ OD, 400 MHz) δ 8.78 (1H, br s), 8.18 (2H, d, J=8.6 Hz), 7.86(1H br s), 7.74 (1H, br d, J=8 Hz), 7.64 (2H, d, J=8.6 Hz), 7.56 (1H, brd, J=8 Hz), 7.46 (1H, br s), 7.44 (1H, dd J=8, 8 Hz), 4.8 (1H, m), 3.74to 3.79 (9H, m), 2.58 to 2.66 (2H, m), 2.23 (1H, m), 2.12 (1H, m), 2.10(3H, s). FAB ms (m+1) 512.

Anal. Calc. for C₂₅ H₂₉ N₅ O₅ S•0.70 H₂ O·3.30 TFA. Found: C, 42.12; H,3.75, N, 7.91.

Step B: Preparation ofN-(1(S)-carboxy-3-methylthiopropyl)-3-[N-(4-imidazolylymethyl)-N-(4-nitrobenzyl)aminomethyl]benzamideditrifluoroacetate

The product from Step A (0.045 g, 0.0608 mmol) was dissolved in methanol(4 mL) and 0.5 mL of 10% NaOH solution was added to take pH to about 12.Water (4 mL) was added. At 3 h reaction was purified and lyophilizedaccording to the procedure described in Step A to the title compound asa white solid. ¹ HNMR (CD₃ OD, 400 MHz) δ 8.78 (1H, br s), 8.18 (2H, d,J=8.6 Hz), 7.88 (1H, br s), 7.75 (1H, br d, J=8 Hz), 7.65 (2H, d, J=8.6Hz), 7.55 (1H, br d, J=8 Hz), 7.46 (1H, br s), 7.43 (1H, dd, J=8, 8 Hz),4.8 (1H, m), 3.80 (4H, br s), 3.75 (2H, br s), 2.58 to 2.68 (2H, m),2.27 (1H, m), 2.13 (1H, m), 2.11 (3H, s). FAB ms (m+1) 498,

Anal Calc. for C₂₄ H₂₇ N₅ O₅ S. 1.40 H₂ O+3.20 TFA. Found: C, 41.16; H,3.72; N, 8.11.

Example 9

N-(1(S)-carboxy-3-methylthiopropyl)-3-[N,N-bis-(4-nitrophenylmethyl)aminomethyl]benzamidedihydrochloride

Step A: Preparation ofN-(1(S)-carboxymethyl-3-methylthiopropyl)-3-[N,N-bis-(4-nitrophenylmethyl)]ditrifluoroacetate

The product from Example 1, Step 3 (0.100 g, 0.337 mmol) was dissolvedin dichloroethane (5 mL). p-Nitrobenzaldehyde, sodiumtriacetoxyborohydride (0.214 g, 1.01 mmol) and crushed molecular sieveswere added, and the pH adjusted to 5.5 with acetic acid andtriethylamine. The reaction was stirred at 20° C. overnight, quenchedwith saturated sodium bicarbonate, and partitioned between ethyl acetateand saturated sodium bicarbonate. The organic phase was washed with 2%potassium hydrogen sulfate, saturated sodium bicarbonate, saturatedbrine, and dried over magnesium sulfate. The crude product was purifiedby silica gel chromatography using 40% ethyl acetate in hexane. Thisproduct was further purified by preparative reverse phase HPLC using agradient elution from 85 % water, 15% acetonitrile to 20% water over aperiod of 40 min. (solvents contained 0.1% trifluoroacetic acid). ¹ HNMR(300 MHz, CDCl₃) d 8.25(4H, d, J=8.5 Hz), 7.92 (1H, s), 7.80 (1H, d,J=7.6 Hz), 7.63 (4H, d, J=8.5 Hz).7.53 (m, 2H), 7.35 (1H, d, J=7.3 Hz),4.94 (1H, bq, J=6.2 Hz), 3.98 (4H, s), 3.95 (2H, s), 3.82 (3H, s), 2.61(2H, t, J=7.3 Hz), 2.30 (1H, m), 2.19 (1H, dt, J=15, 7.5 Hz), 2.11 (3H,s).

Analysis calculated for C₂₈ H₃₀ N₄ O₇ S•2.1 CF₃ CO₂ H•0.5 H₂ O: C,47.45;H, 4.09; N, 6.87. Found: C, 47.44; H, 4.01;N, 6.91.

Step B: Preparation ofN-(1(S)-carboxy-3-methylthiopropyl)-3-[N,N-bis-(4-nitrophenylmethyl)aminomethyl]benzamideditrifluoroacetate

The product from Step 1 (0.025 g) was hydrolyzed to the acid accordingto the procedure described in Example 1, Step 6. The title compound wasobtained after purification by preparative reverse phase HPLC. FAB msm/e (m+1) 553).

Analysis calculated for C₂₇ H₂₈ N₄ O₇ S•1.6 CF₃ CO₂ H•0.2 H₂ O: C,49.11; H, 4.09; N, 7.59. Found: C, 49.10; H, 3.93; N, 7.55.

Example 10

In vitro inhibition of ras farnesyl transferase

Assays of farnesyl-protein transferase. Partially purified bovine FPTaseand Ras peptides (Ras-CVLS, Ras-CVIM and RAS-CAIL) were prepared asdescribed by Schaber et al., J. Biol. Chem. 265:14701-14704 (1990),Pompliano, et al., Biochemistry 31:3800 (1992) and Gibbs et al., PNASU.S.A. 86:6630-6634 (1989), respectively. Bovine FPTase was assayed in avolume of 100 μl containing 100 mM N-(2-hydroxy ethyl)piperazine-N'-(2-ethane sulfonic acid) (HEPES), pH 7.4, 5 mM MgCl₂, 5 mMdithiothreitol (DTT), 100 mM [³ H]-farnesyl diphosphate ([³ H]-FPP; 740CBq/mmol, New England Nuclear), 650 nM Ras-CVLS and 10 μg/ml FPTase at31 ° C. for 60 min. Reactions were initiated with FPTase and stoppedwith 1 ml of 1.0M HCL in ethanol. Precipitates were collected ontofilter-mats using a TomTec Mach II cell harvestor, washed with 100%ethanol, dried and counted in an LKB β-plate counter. The assay waslinear with respect to both substrates, FPTase levels and time; lessthan 10% of the [³ H]-FPP was utilized during the reaction period.Purified compounds were dissolved in 100% dimethyl sulfoxide (DMSO) andwere diluted 20-fold into the assay. Percentage inhibition is measuredby the amount of incorporation of radioactivity in the presence of thetest compound when compared to the amount of incorporation in theabsence of the test compound.

Human FPTase was prepared as described by Omer et al., Biochemistry32:5167-5176 (1993). Human FPTase activity was assayed as describedabove with the exception that 0.1% (w/v) polyethylene glycol 20,000, 10μM ZnCl₂ and 100 nM Ras-CVIM were added to the reaction mixture.Reactions were performed for 30 min., stopped with 100 μl of 30% (v/v)trichloroacetic acid (TCA) in ethanol and processed as described abovefor the bovine enzyme.

The compounds of the instant invention were tested for inhibitoryactivity against human FPTase by the assay described above and werefound to have IC₅₀ of <100 μM.

Example 11

In vivo ras farnesylation assay

The cell line used in this assay is a v-ras line derived from eitherRat1 or NIH3T3 cells, which expressed viral Ha-ras p21. The assay isperformed essentially as described in DeClue, J. E. et al., CancerResearch 51:712-717, (1991). Cells in 10 cm dishes at 50-75% confluencyare treated with the test compound (final concentration of solvent,methanol or dimethyl sulfoxide, is 0.1%). After 4 hours at 37° C., thecells are labelled in 3 ml methionine-free DMEM supple-meted with 10%regular DMEM, 2% fetal bovine serum and 400 mCi[³⁵ S]methionine (1000Ci/mmol). After an additional 20 hours, the cells are lysed in 1 mllysis buffer (1% NP40/20 mM HEPES, pH 7.5/5 mM MgCl₂ /1 mM DTT/10 mg/mlaprotinen/2 mg/ml leupeptin/2 mg/ml antipain/0.5 mM PMSF) and thelysates cleared by centrifugation at 100,000×g for 45 min. Aliquots oflysates containing equal numbers of acid-precipitable counts are boughtto 1 ml with IP buffer (lysis buffer lacking DTT) and immunoprecipitatedwith the ras-specific monoclonal antibody Y13-259 (Furth, M. E. et al.,J. Virol. 43:294-304, (1982)). Following a 2 hour antibody incubation at4° C., 200 ml of a 25% suspension of protein A-Sepharose coated withrabbit anti rat IgG is added for 45 min. The immunoprecipitates arewashed four times with IP buffer (20 nM HEPES, pH 7.5/1 mM EDTA/1%Triton X-100.0.5% deoxycholate/0.1%/SDS/0.1M NaCl) boiled in SDS-PAGEsample buffer and loaded on 13% acrylamide gels. When the dye frontreached the bottom, the gel is fixed, soaked in Enlightening, dried andautoradiographed. The intensities of the bands corresponding tofarnesylated and nonfarnesylated ras proteins are compared to determinethe percent inhibition of farnesyl transfer to protein.

Example 12

In vivo growth inhibition assay

To determine the biological consequences of FPTase inhibition, theeffect of the compounds of the instant invention on theanchorage-independent growth of Rat1 cells transformed with either av-ras, v-raf, or v-mos oncogene is tested. Cells transformed by v-Rafand v-Mos maybe included in the analysis to evaluate the specificity ofinstant compounds for Ras-induced cell transformation.

Rat 1 cells transformed with either v-ras, v-raf, or v-mos are seeded ata density of 1×10⁴ cells per plate (35 mm in diameter) in a 0.3% topagarose layer in medium A (Dulbecco's modified Eagle's mediumsupplemented with 10% fetal bovine serum) over a bottom agarose layer(0.6%). Both layers contain 0.1% methanol or an appropriateconcentration of the instant compound (dissolved in methanol at 1000times the final concentration used in the assay). The cells are fedtwice weekly with 0.5 ml of medium A containing 0.1% methanol or theconcentration of the instant compound. Photomicrographs are taken 16days after the cultures are seeded and comparisons are made.

What is claimed is:
 1. A compound which inhibits Rasfarnesyl-transferase having the Formula I: ##STR30## wherein: R^(1a) andR^(1b) are independently selected from:a) hydrogen, b) aryl,heterocycle, cycloalkyl, alkenyl, alkynyl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, c) C₁ -C₆ alkyl, and d) C₁ -C₆ alkylsubstituted by a group selected from: aryl, heterocyclic, cycloalkyl,alkenyl, alkynyl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, (R¹⁰)₂N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)--NR¹⁰--; R^(2a) and R^(2b) are independently selected from:a) hydrogen, b) C₁-C₆ alkyl, c) C₁ -C₆ alkyl substituted by a group selected from:alkenyl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, N₃, (R¹⁰)₂N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,d) aryl, heterocycle, cycloalkyl, alkenyl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and e) C₁ -C₆ alkyl substituted with a agroup selected from:i) aryl, ii) substituted aryl, iii) heterocyclic,iv) substituted heterocyclic, v) C₃ -C₁₀ cycloalkyl, and vi) substitutedC₃ -C₁₀ cycloalkyl; R^(3a) and R^(3b) are independently selected from:a)a side chain of a naturally occurring amino acid, b) an oxidized form ofa side chain of a naturally occurring amino acid which is:i) methioninesulfoxide, or ii) methionine sulfone, and c) a group selected from C₁-C₂₀ alkyl, C₂ -C₂₀ alkenyl, C₃ -C₁₀ cycloalkyl, aryl or heterocyclicgroup, the group which is substituted with a substituent is selectedfrom F, Cl, Br, N(R¹⁰)₂, NO₂, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,CN, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, R¹¹OC(O)NR¹⁰ -- and C₁ -C₂₀ alkyl, d) a group selected from C₁ -C₂₀ alkyl,C₂ -C₂₀ alkenyl, C₃ -C₁₀ cycloalkyl, aryl or heterocyclic group, and e)C₁ -C₆ alkyl substituted with a a group selected from:i) aryl, ii)substituted aryl, iii) heterocyclic, iv) substituted heterocyclic, v) C₃-C₁₀ cycloalkyl, and vi) substituted C₃ -C₁₀ cycloalkyl;or R^(3a) andR^(3b) are combined to form --(CH₂)_(s) -- or --(CH₂)_(s) -- wherein oneof the carbon atoms is replaced by a moiety selected from: O, S(O)_(m),--NC(O)--, and --N(COR¹⁰)--; R⁴ and R⁵ are independently selectedfrom:a) hydrogen, and b) ##STR31## R⁷ is independently selected from: a)hydrogen, b) aryl, heterocycle, cycloalkyl, alkenyl, alkynyl,perfluoroalkyl, F, Cl, Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,CN, NO₂, R¹⁰ ₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, orR¹¹ OC(O)NR¹⁰ --, c) C₁ -C₆ alkyl, and d) C₁ -C₆ alkyl substituted by agroup selected from: aryl, heterocycle, cycloalkyl, alkenyl, alkynyl,perfluoroalkyl, F, Cl, Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NH--, CN,H₂ N--C(NH)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, or R¹⁰ OC(O)NH--;R⁸ is selected from:a) hydrogen, b) alkenyl, alkynyl, perfluoroalkyl, F,Cl, Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂N--C--(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰--, c) C₁ -C₆ alkyl, and d) C₁ -C₆ alkyl substituted by a group selectedfrom: perfluoroalkyl, F, Cl, Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, CN, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, orR¹¹ OC(O)NR¹⁰ --; R¹⁰ is independently selected from hydrogen, C₁ -C₆alkyl, benzyl and aryl; R¹¹ is independently selected from C₁ -C₆ alkyland aryl; A¹ and A² are independently selected from: a bond, --CH═CH--,--C.tbd.C--, --C(O)--, --C(O)NR¹⁰ --, --NR¹⁰ C(O)--, O, --N(R¹⁰)--,--S(O)₂ N(R¹⁰)--, --N(R¹⁰)S(O)₂ --, or S(O)_(m) ; V is selected from:a)hydrogen, b) heterocyele, c) aryl, d) C₁ -C₂₀ alkyl wherein from 0 to 4carbon atoms are replaced with a a heteroatom selected from O, S, and N,and e) C₂ -C₂₀ alkenyl,provided that V is not hydrogen if A¹ is S(O)_(m)and V is not hydrogen if A¹ is a bond, n is 0 and A² is S(O)_(m) ; W isa heterocycle; Z is independently H₂ or O; m is 0, 1 or 2; n is 0, 1, 2,3 or 4; p is 0, 1, 2, 3 or 4; r is 0 to 5, provided that r is 0 when Vis hydrogen; s is 4 or 5; and u is 0 or 1;or a pharmaceuticallyacceptable salt thereof.
 2. A compound which inhibits Rasfarnesyl-transferase having the Formula III: ##STR32## wherein: R^(1a)and R^(1b) are independently selected from:a) hydrogen, b) aryl,heterocycle, cycloalkyl, alkenyl, alkynyl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃,N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, c) C₁ -C₆ alkyl, and d) C₁ -C₆ alkylsubstituted by a group selected from: aryl, heterocyclic, cycloalkyl,alkenyl, alkynyl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, (R¹⁰)₂N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)--NR¹⁰--; R^(2a) and R^(2b) are independently selected from:a) hydrogen. b) C₁-C₆ alkyl; c) C₁ -C₆ alkyl substituted by a group selected from:alkenyl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, N₃, (R¹⁰)₂N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,d) aryl, heterocycle, cycloalkyl, alkenyl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and e) C₁ -C₆ alkyl substituted with a agroup selected from:i) aryl, ii) substituted aryl, iii) heterocyclic,iv) substituted heterocyclic, v) C₃ -C₁₀ cycloalkyl, and vi) substitutedC₃ -C₁₀ cycloalkyl; R⁴ and R⁵ are independently selected from:a)hydrogen, and b) ##STR33## R⁷ is independently selected from: a)hydrogen, b) aryl, heterocycle, cycloalkyl, alkenyl, alkynyl,perfluoroalkyl, F, Cl, Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,CN, NO₂, R¹⁰ ₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, orR¹¹ OC(O)NR¹⁰ --, c) C₁ -C₆ alkyl, and d) C₁ -C₆ alkyl substituted by agroup selected from: aryl, heterocycle, cycloalkyl, alkenyl, alkynyl,perfluoroalkyl, F, Cl, Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NH--, CN,H₂ N--C(NH)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, or R¹⁰ OC(O)NH--;R⁸ is selected from:a) hydrogen, b) alkenyl, alkynyl, perfluoroalkyl, F,Cl, Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂N--C--(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰--, c) C₁ -C₆ alkyl, and d) C₁ -C₆ alkyl substituted by a group selectedfrom: perfluoroalkyl, F, Cl, Br, R¹⁰ O--, R¹¹ S(O)m--, R¹⁰ C(O)NR¹⁰ --,CN, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰ --; R¹⁰ is independently selected from hydrogen, C₁ -C₆ alkyl,benzyl and aryl; R¹¹ is independently selected from C₁ -C₆ alkyl andaryl; A¹ and A² are independently selected from: a bond, --CH═CH--,--C.tbd.C--, --C(O)--, --C(O)NR¹⁰ --, --NR¹⁰ C(O)--, O, --N(R¹⁰)--,--S(O)₂ N(R¹⁰)--, --N(R¹⁰)S(O)₂ --, or S(O)_(m) ; V is selected from:a)hydrogen, b) heterocycle, c) aryl, d) C₁ -C₂₀ alkyl wherein from 0 to 4carbon atoms are replaced with a a heteroatom selected from O, S, and N,and e) C₂ -C₂₀ alkenyl,provided that V is not hydrogen if A¹ is S(O)_(m)and V is not hydrogen if A¹ is a bond, n is 0 and A² is S(O)_(m) ; W isa heterocycle; Z is independently H₂ or O; m is 0, 1 or 2; n is 0, 1, 2,3 or 4; p is 0, 1, 2, 3 or 4; q is 0, 1 or 2; r is 0 to 5, provided thatr is 0 when V is hydrogen; s is 4 or 5; and u is 0 or 1;or apharmaceutically acceptable salt thereof.
 3. The compound according toclaim 1 of the formula Ia: ##STR34## wherein: R^(1a) is independentlyselected from: hydrogen or C₁ -C₆ alkyl;R^(1b) is independently selectedfrom:a) hydrogen, b) aryl, heterocycle, cycloalkyl, R¹⁰ O--, --N(R¹⁰)₂or alkenyl, c) C₁ -C₆ alkyl, and d) C₁ -C₆ alkyl substituted by a groupselected from: aryl, heterocycle, cycloalkyl, alkenyl, R¹⁰ O--, or--N(R¹⁰)₂ ; R^(2a) is selected from:a) hydrogen, b) C₁ -C₆ alkyl, c) C₁-C₆ alkyl substituted by a group selected from: alkenyl, R¹⁰ O--, R¹¹S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, N₃, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--,R¹⁰ OC(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, d) aryl, heterocycle,cycloalkyl, alkenyl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, NO₂,(R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O) --, N₃, --N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰ --, and e) C₁ -C₆ alkyl substituted with a a group selectedfrom:i) aryl, ii) substituted aryl, iii) heterocyclic, iv) substitutedheterocyclic, v) C₃ -C₁₀ cycloalkyl, and vi) substituted C₃ -C₁₀cycloalkyl; R^(2b) is hydrogen; R^(3a) and R^(3b) are independentlyselected from:a) a side chain of a naturally occurring amino acid, b) anoxidized form of a side chain of a naturally occurring amino acid whichis:i) methionine sulfoxide, or ii) methionine sulfone, c) a groupselected from C₁ -C₂₀ alkyl, C₂ -C₂₀ alkenyl, C₃ -C₁₀ cycloalkyl, arylor heterocyclic group, the group which is substituted with a substituentis selected from F, Cl, Br, N(R¹⁰)₂, NO₂, R¹⁰ O--, R¹¹ S(O)_(m) --,--R¹⁰ C(O)NR¹⁰ --, CN, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃,--N(R¹⁰)₂, R¹¹ OC(O)NR¹⁰ -- and C₁ -C₂₀ alkyl, d) a group selected fromC₁ -C₂₀ alkyl, C₂ -C₂₀ alkenyl, C₃ -C₁₀ cycloalkyl, aryl or heterocyclicgroup, and e) C₁ -C₆ alkyl substituted with a a group selected from:i)aryl, ii) substituted aryl, iii) heterocyclic, iv) substitutedheterocyclic, v) C₃ -C₁₀ cycloalkyl, and vi) substituted C₃ -C₁₀cycloalkyl; R⁴ and R⁵ are independently selected from:a) hydrogen, andb) ##STR35## R⁷ is independently selected from: a) hydrogen, b) C₁ -C₆alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₁ -C₆ perfluoroalkyl, F, Cl, R¹⁰O--, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰OC(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and c) C₁ -C₆ alkyl substitutedby C₁ -C₆ perfluoroalkyl, R¹⁰ O--, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ N--C(NR¹⁰)--,R¹⁰ C(O)--, R¹⁰ OC(O)(--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ 13 ; R⁸ isselected from:a) hydrogen, b) C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₁ -C₆perfluoroalkyl, F, Cl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN,NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, --N(R¹⁰)₂, or R¹¹OC(O)NR₁₀ --, c) C₁ -C₆ alkyl; and d) C₁ -C₆ alkyl substituted by agroup selected from: C₁ -C₆ perfluoroalkyl, F, Cl, R¹⁰ O--, R¹¹ S(O)_(m)--, R¹⁰ C(O)NR¹⁰, CN, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --; R¹⁰ is independently selected fromhydrogen, C₁ -C₆ alkyl, benzyl and aryl; R¹¹ is independently selectedfrom C₁ -C₆ alkyl and aryl; A¹ and A² are independently selected from: abond, --CH═CH--, --C.tbd.C--, --C(O)--, --C(O)NR¹⁰ --, O, --N(R¹⁰)--, orS(O)_(m) ; V is selected from:a) hydrogen, b) heterocycle selected frompyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl,2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, c)aryl, d) C₁ -C₂₀ alkyl wherein from 0 to 4 carbon atoms are replacedwith a a heteroatom selected from O, S, and N, and e) C₂ -C₂₀ alkenyl,andprovided that V is not hydrogen if A¹ is S(O)_(m) and V is nothydrogen if A¹ is a bond, n is 0 and A² is S(O)_(m) ; W is a heterocycleselected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl,2-oxopiperidinyl, indolyl, quinolinyl, or isoquinolinyl; Z isindependently H₂ or O; m is 0, 1 or 2; n is 0, 1, 2, 3 or 4; p is 0, 1,2, 3 or 4; r is 0 to 5, provided that r is 0 when V is hydrogen; and uis 0or 1;or a pharmaceutically acceptable salt thereof.
 4. The compoundaccording to claim 2 of the formula IIIa: ##STR36## wherein: R^(1a) isindependently selected from: hydrogen or C₁ -C₆ alkyl;R^(1b) isindependently selected from:a) hydrogen, b) aryl, heterocycle,cycloalkyl, R¹⁰ O--, --N(R¹⁰)₂ or alkenyl, c) C₁ -C₆ alkyl, and d) C₁-C₆ alkyl substituted by a group selected from: aryl, heterocycle,cycloalkyl, alkenyl, R¹⁰ O--, or --N(R¹⁰)₂ ; R^(2a) is selected from:a)hydrogen, b) C₁ -C₆ alkyl, c) C₁ -C₆ alkyl substituted by a groupselected from: alkenyl, R¹⁰ O--, R¹¹ S(O)m--, R¹⁰ C(O)NR¹⁰ --, CN, N₃,(R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, --N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰ --, d) aryl, heterocycle, cycloalkyl, alkenyl, R¹⁰ O--, R¹¹S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--,R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and e) C₁ -C₆ alkylsubstituted with a a group selected from:i) aryl, ii) substituted aryl,iii) heterocyclic, iv) substituted heterocyclic, v) C₃ -C₁₀ cycloalkyl,and vi) substituted C₃ -C₁₀ cycloalkyl; R^(2b) is hydrogen; R⁴ and R⁵are independently selected from:a) hydrogen, and b) ##STR37## R⁷ isindependently selected from: a) hydrogen, b) C₁ -C₆ alkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, C₁ -C₆ perfluoroalkyl, F, Cl, R¹⁰ O--, R¹⁰C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and c) C₁ -C₆ alkyl substituted by C₁-C₆ perfluoroalkyl, R¹⁰ O--, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰C(O)--, R¹⁰ OC(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --; R⁸ is selectedfrom:a) hydrogen, b) C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₁ -C₆perfluoroalkyl, F, Cl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN,NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, --N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰ --, c) C₁ -C₆ alkyl; and d) C₁ -C₆ alkyl substituted by agroup selected from: C₁ -C₆ perfluoroalkyl, F, Cl, R¹⁰ O--, R¹¹ S(O)_(m)--, R¹⁰ C(O)NR¹⁰ --, CN, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --; R¹⁰ is independently selected fromhydrogen, C₁ -C₆ alkyl, benzyl and aryl; R¹¹ is independently selectedfrom C₁ -C₆ alkyl and aryl; A¹ and A² are independently selected from: abond, --CH═CH--, --C.tbd.C--, --C(O)--, --C(O)NR¹⁰ --, O, --N(R¹⁰)--, orS(O)_(m) ; V is selected from:a) hydrogen, b) heterocycle selected frompyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl,2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, c)aryl, d) C₁ -C₂₀ alkyl wherein from 0 to 4 carbon atoms are replacedwith a a heteroatom selected from O, S, and N, and e) C₂ -C₂₀ alkenyl,andprovided that V is not hydrogen if A¹ is S(O)_(m) and V is nothydrogen if A¹ is a bond, n is 0 and A² is S(O)_(m) ; W is a heterocycleselected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl,2-oxopiperidinyl, indolyl, quinolinyl, or isoquinolinyl; Z isindependently H₂ or O; m is 0, 1 or 2; n is 0, 1, 2, 3 or 4; p is 0, 1,2, 3 or 4; q is 0, 1 or 2; r is 0 to 5, provided that r is 0 when V ishydrogen; and u is 0 or 1;or a pharmaceutically acceptable salt thereof.5. A compound which inhibits farnesyl-protein transferase whichis:N-(1(S)-carboxy-3-methylthiopropyl)-3-(4-imidazolylmethyl)aminomethylbenzamideN-(1(S)-carboxy-3-methylthiopropyl)-3-[N,N-bis-(4-imidazolemethyl)aminomethyl]benzamideN-(1(S)-carboxy-3-methylthiopropyl)3-[(4-imidazolylmethyl)-N-methylaminomethyl]benzamideN-(1(S)-carboxy-3-methylthiopropyl)-4-[(4-imidazolylmethyl)amino]benzamideN-(1(S)-carboxy-3-methylthiopropyl)-3-[(4-imidazolylmethyl)amino]benzamideN-(1(S)-Carboxy-3-methylthiopropyl)-3-[(4-imidazolylpropyl)amino]benzamideN-(1(S)-Carboxy-3-methylthiopropyl)-3-[N-(4-imidazolylymethyl)-N-(4-nitrobenzyl)aminomethyl]benzamideN-(1(S)-carboxy-3-methylthiopropyl)-3-[N,N-bis-(4-nitrophenylmethyl)aminomethyl]benzamideoror a pharmaceutically acceptable salt thereof.
 6. A compound accordingto claim 5 which inhibits farnesyl-protein transferase whichis:N-(1(S)-carboxy-3-methylthiopropyl)-3-[N,N-bis-(4-nitrophenylmethyl)]aminomethylbenzamide##STR38## or a pharmaceutically acceptable salt thereof.
 7. A compoundaccording to claim 5 which inhibits farnesyl-protein transferase whichis:N-(1(S)-carboxy-3-methylthiopropyl)-3-[N,N-bis(4-imidazolemethyl)aminomethyl]benzamide##STR39## or a pharmaceutically acceptable salt thereof.
 8. A compoundaccording to claim 5 which inhibits farnesyl-protein transferase whichis:N-(1(S)-Carboxy-3-methylthiopropyl)-3-[N-(4-imidazolylymethyl)-N-(4-nitrobenzyl)aminomethyl]benzamide##STR40## or a pharmaceutically acceptable salt thereof.
 9. Apharmaceutical composition comprising a pharmaceutical carrier, anddispersed therein, a therapeutically effective amount of a compound ofclaim
 1. 10. A pharmaceutical composition comprising a pharmaceuticalcarrier, and dispersed therein, a therapeutically effective amount of acompound of claim
 2. 11. A pharmaceutical composition comprising apharmaceutical carrier, and dispersed therein, a therapeuticallyeffective amount of a compound of claim
 5. 12. A method for inhibitingfarnesylation of Ras protein which comprises administering to a mammalin need thereof a therapeutically effective amount of the composition ofclaim
 9. 13. A method for inhibiting farnesylation of Ras protein whichcomprises administering to a mammal in need thereof a therapeuticallyeffective amount of the composition of claim
 10. 14. A method forinhibiting farnesylation of Ras protein which comprises administering toa mammal in need thereof a therapeutically effective amount of thecomposition of claim
 11. 15. A method for treating cancer whichcomprises administering to a mammal in need thereof a therapeuticallyeffective amount of a composition of claim
 9. 16. A method for treatingcancer which comprises administering to a mammal in need thereof atherapeutically effective amount of a composition of claim
 10. 17. Amethod for treating cancer which comprises administering to a mammal inneed thereof a therapeutically effective amount of a composition ofclaim 11.